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Dave, Sandeep S.

Positions:

Professor of Medicine

Medicine, Hematological Malignancies
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1999

M.D. — Northwestern University

Medical Resident, Medicine

Northwestern University

Fellow In Hematology Oncology, Medicine

National Institutes of Health

News:

Grants:

Genetic and genomic signatures of long-term radiation exposure in non-human primates

Administered By
Medicine, Hematological Malignancies
AwardedBy
Wake Forest University School Of Medicine
Role
Principal Investigator
Start Date
September 30, 2015
End Date
September 29, 2020

Defining the Functional Role of Mutations in Diffuse Large B cell Lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2020

Understanding the Context-Dependent Roles of Mutations in Lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 18, 2009
End Date
August 31, 2019

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1980
End Date
June 30, 2019

Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 15, 2016
End Date
August 31, 2018

Dissecting the role of injury is sarcoma formation

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Sarcoma Alliance for Research Through Collaboration
Role
Collaborator
Start Date
July 01, 2015
End Date
August 31, 2017

Dissecting the role of injury is sarcoma formation

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Sarcoma Alliance for Research Through Collaboration
Role
Collaborator
Start Date
July 01, 2015
End Date
August 31, 2017

HARDAC+:Reproducible HPC for next-generation genomics

Administered By
Duke Center for Genomic and Computational Biology
AwardedBy
North Carolina Biotechnology Center
Role
Major User
Start Date
April 15, 2016
End Date
April 14, 2017

The genetics of hepatosplenic T cell lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2017

Phase 1 Trial of Panobinostat + Ruxolitnib for Relapsed/Refactory Diffused Large B Cell Lymphoma (DLBCL)

Administered By
Medicine, Hematological Malignancies
AwardedBy
Lymphoma Research Foundation of America
Role
Mentor
Start Date
March 01, 2016
End Date
February 28, 2017

Genetic determinants of progression in chronic lymphocytic leukemia

Administered By
Medicine, Hematological Malignancies
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
November 01, 2012
End Date
October 31, 2016

Novel combinations to overcome resistance to histone deacetylase inhibitors in lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
Leukemia & Lymphoma Society
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2016

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2016

Predicting Treatment Futility in Refractory Diffuse Large B cell Lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
Leukemia & Lymphoma Society
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2015

Clinico-Genomic Assessment of Performance Status in Elderly AML Patients

Administered By
Center for the Study of Aging and Human Development
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 01, 2012
End Date
August 31, 2015

Exome-wide screening for common mutations in lymphoma

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 10, 2011
End Date
May 31, 2013
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Publications:

GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo.

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

Authors
Healy, JA; Nugent, A; Rempel, RE; Moffitt, AB; Davis, NS; Jiang, X; Shingleton, JR; Zhang, J; Love, C; Datta, J; McKinney, ME; Tzeng, TJ; Wettschureck, N; Offermanns, S; Walzer, KA; Chi, J-T; Rasheed, SAK; Casey, PJ; Lossos, IS; Dave, SS
MLA Citation
Healy, JA, Nugent, A, Rempel, RE, Moffitt, AB, Davis, NS, Jiang, X, Shingleton, JR, Zhang, J, Love, C, Datta, J, McKinney, ME, Tzeng, TJ, Wettschureck, N, Offermanns, S, Walzer, KA, Chi, J-T, Rasheed, SAK, Casey, PJ, Lossos, IS, and Dave, SS. "GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo." Blood 127.22 (June 2016): 2723-2731.
PMID
26989201
Source
epmc
Published In
Blood
Volume
127
Issue
22
Publish Date
2016
Start Page
2723
End Page
2731
DOI
10.1182/blood-2015-07-659938

SMRT Sequencing for Parallel Analysis of Multiple Targets and Accurate SNP Phasing.

Single-molecule real-time (SMRT) sequencing generates much longer reads than other widely used next-generation (next-gen) sequencing methods, but its application to whole genome/exome analysis has been limited. Here, we describe the use of SMRT sequencing coupled with barcoding to simultaneously analyze one or a small number of genomic targets derived from multiple sources. In the budding yeast system, SMRT sequencing was used to analyze strand-exchange intermediates generated during mitotic recombination and to analyze genetic changes in a forward mutation assay. The general barcoding-SMRT approach was then extended to diffuse large B-cell lymphoma primary tumors and cell lines, where detected changes agreed with prior Illumina exome sequencing. A distinct advantage afforded by SMRT sequencing over other next-gen methods is that it immediately provides the linkage relationships between SNPs in the target segment sequenced. The strength of our approach for mutation/recombination studies (as well as linkage identification) derives from its inherent computational simplicity coupled with a lack of reliance on sophisticated statistical analyses.

Authors
Guo, X; Lehner, K; O'Connell, K; Zhang, J; Dave, SS; Jinks-Robertson, S
MLA Citation
Guo, X, Lehner, K, O'Connell, K, Zhang, J, Dave, SS, and Jinks-Robertson, S. "SMRT Sequencing for Parallel Analysis of Multiple Targets and Accurate SNP Phasing." G3 (Bethesda, Md.) 5.12 (October 23, 2015): 2801-2808.
PMID
26497143
Source
epmc
Published In
G3 (Bethesda, Md.)
Volume
5
Issue
12
Publish Date
2015
Start Page
2801
End Page
2808
DOI
10.1534/g3.115.023317

The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma.

Epstein-Barr virus (EBV) infection is a common feature of B cell lymphoproliferative disorders (LPDs), including diffuse large B cell lymphoma. Approximately 10 % of DLBCLs are EBV-positive, with the highest incidence in immunocompromised and elderly patients. Here, we review the clinical, genetic, and pathologic characteristics of DLBCL and discuss the molecular role of EBV in lymphoma tumorigenesis. Using EBV-positive DLBCL of the elderly as a model, we describe the key features of EBV-positive DLBCL. Studies of EBV-positive DLBCL of the elderly demonstrate that EBV-positive DLBCL has a distinct biology, related to both viral and host factors. The pathogenic mechanisms noted in EBV-positive DLBCL of the elderly, including enhanced NFκB activity, are likely to be a generalizable feature of EBV-positive DLBCL. Therefore, we review how this information might be used to target the EBV or its host response for the development of novel treatment strategies.

Authors
Healy, JA; Dave, SS
MLA Citation
Healy, JA, and Dave, SS. "The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma." Current topics in microbiology and immunology 390.Pt 1 (January 2015): 315-337. (Review)
PMID
26424652
Source
epmc
Published In
Current topics in microbiology and immunology
Volume
390
Issue
Pt 1
Publish Date
2015
Start Page
315
End Page
337
DOI
10.1007/978-3-319-22822-8_13

A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes.

Human erythrocytes are terminally differentiated, anucleate cells long thought to lack RNAs. However, previous studies have shown the persistence of many small-sized RNAs in erythrocytes. To comprehensively define the erythrocyte transcriptome, we used high-throughput sequencing to identify both short (18-24 nt) and long (>200 nt) RNAs in mature erythrocytes.Analysis of the short RNA transcriptome with miRDeep identified 287 known and 72 putative novel microRNAs. Unexpectedly, we also uncover an extensive repertoire of long erythrocyte RNAs that encode many proteins critical for erythrocyte differentiation and function. Additionally, the erythrocyte long RNA transcriptome is significantly enriched in the erythroid progenitor transcriptome. Joint analysis of both short and long RNAs identified several loci with co-expression of both microRNAs and long RNAs spanning microRNA precursor regions. Within the miR-144/451 locus previously implicated in erythroid development, we observed unique co-expression of several primate-specific noncoding RNAs, including a lncRNA, and miR-4732-5p/-3p. We show that miR-4732-3p targets both SMAD2 and SMAD4, two critical components of the TGF-β pathway implicated in erythropoiesis. Furthermore, miR-4732-3p represses SMAD2/4-dependent TGF-β signaling, thereby promoting cell proliferation during erythroid differentiation.Our study presents the most extensive profiling of erythrocyte RNAs to date, and describes primate-specific interactions between the key modulator miR-4732-3p and TGF-β signaling during human erythropoiesis.

Authors
Doss, JF; Corcoran, DL; Jima, DD; Telen, MJ; Dave, SS; Chi, J-T
MLA Citation
Doss, JF, Corcoran, DL, Jima, DD, Telen, MJ, Dave, SS, and Chi, J-T. "A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes." BMC genomics 16 (January 2015): 952-.
PMID
26573221
Source
epmc
Published In
BMC Genomics
Volume
16
Publish Date
2015
Start Page
952
DOI
10.1186/s12864-015-2156-2

Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex® system.

Authors
Collie, AMB; Nölling, J; Divakar, KM; Lin, JJ; Carver, P; Durkin, LM; Hill, BT; Smith, MR; Radivoyevitch, T; Kong, LI; Daly, T; Murugesan, G; Guenther-Johnson, J; Dave, SS; Manilich, EA; Hsi, ED
MLA Citation
Collie, AMB, Nölling, J, Divakar, KM, Lin, JJ, Carver, P, Durkin, LM, Hill, BT, Smith, MR, Radivoyevitch, T, Kong, LI, Daly, T, Murugesan, G, Guenther-Johnson, J, Dave, SS, Manilich, EA, and Hsi, ED. "Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex® system." British journal of haematology 167.2 (October 2014): 281-285. (Letter)
PMID
24961756
Source
epmc
Published In
British Journal of Haematology
Volume
167
Issue
2
Publish Date
2014
Start Page
281
End Page
285
DOI
10.1111/bjh.12983

New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing.

PURPOSE OF REVIEW: Burkitt lymphoma is an important clinical and model disease arising from B cells. Burkitt lymphoma is characterized by translocation of the c-MYC gene to an immunoglobulin enhancer region, resulting in enhanced cell proliferation and rapid tumor progression. The development of deep sequencing has widened the scope of genetic analysis to reveal the role of additional collaborating mutations in Burkitt lymphoma. In this review, we examine the role of additional genetic events that cooperate with MYC in Burkitt lymphoma pathogenesis. RECENT FINDINGS: Next-generation sequencing of Burkitt lymphoma has identified recurrent silencing mutations in ID3, a novel tumor suppressor gene. In addition, mutations in a number of genes including GNA13, TP53, and SMARCA4 occur in Burkitt lymphoma. Copy number status has implicated recurrent aberrations including gains of 1q and 18q and deletion of 19p13. Additionally, microRNA and gene expression profiling has revealed unique transcriptome signatures in Burkitt lymphoma subgroups. SUMMARY: Analysis of genetic alterations in Burkitt lymphoma has yielded a better understanding of the pathogenesis of this disease. These observations could lead to more effective strategies for the diagnosis and treatment of Burkitt lymphoma.

Authors
Greenough, A; Dave, SS
MLA Citation
Greenough, A, and Dave, SS. "New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing." Current opinion in hematology 21.4 (July 2014): 326-332.
PMID
24867287
Source
epmc
Published In
Current Opinion in Hematology
Volume
21
Issue
4
Publish Date
2014
Start Page
326
End Page
332
DOI
10.1097/moh.0000000000000059

New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing

Authors
Greenough, A; Dave, SS
MLA Citation
Greenough, A, and Dave, SS. "New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing." Current Opinion in Hematology 21.4 (July 2014): 326-332.
Source
crossref
Published In
Current Opinion in Hematology
Volume
21
Issue
4
Publish Date
2014
Start Page
326
End Page
332
DOI
10.1097/MOH.0000000000000059

Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis.We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib.Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).

Authors
Woyach, JA; Furman, RR; Liu, T-M; Ozer, HG; Zapatka, M; Ruppert, AS; Xue, L; Li, DH-H; Steggerda, SM; Versele, M; Dave, SS; Zhang, J; Yilmaz, AS; Jaglowski, SM; Blum, KA; Lozanski, A; Lozanski, G; James, DF; Barrientos, JC; Lichter, P; Stilgenbauer, S; Buggy, JJ; Chang, BY; Johnson, AJ; Byrd, JC
MLA Citation
Woyach, JA, Furman, RR, Liu, T-M, Ozer, HG, Zapatka, M, Ruppert, AS, Xue, L, Li, DH-H, Steggerda, SM, Versele, M, Dave, SS, Zhang, J, Yilmaz, AS, Jaglowski, SM, Blum, KA, Lozanski, A, Lozanski, G, James, DF, Barrientos, JC, Lichter, P, Stilgenbauer, S, Buggy, JJ, Chang, BY, Johnson, AJ, and Byrd, JC. "Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib." The New England journal of medicine 370.24 (June 2014): 2286-2294.
PMID
24869598
Source
epmc
Published In
The New England journal of medicine
Volume
370
Issue
24
Publish Date
2014
Start Page
2286
End Page
2294
DOI
10.1056/nejmoa1400029

The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.

In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Authors
Zhang, J; Jima, D; Moffitt, AB; Liu, Q; Czader, M; Hsi, ED; Fedoriw, Y; Dunphy, CH; Richards, KL; Gill, JI; Sun, Z; Love, C; Scotland, P; Lock, E; Levy, S; Hsu, DS; Dunson, D; Dave, SS
MLA Citation
Zhang, J, Jima, D, Moffitt, AB, Liu, Q, Czader, M, Hsi, ED, Fedoriw, Y, Dunphy, CH, Richards, KL, Gill, JI, Sun, Z, Love, C, Scotland, P, Lock, E, Levy, S, Hsu, DS, Dunson, D, and Dave, SS. "The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells." Blood 123.19 (May 2014): 2988-2996.
PMID
24682267
Source
epmc
Published In
Blood
Volume
123
Issue
19
Publish Date
2014
Start Page
2988
End Page
2996
DOI
10.1182/blood-2013-07-517177

The polyphony of BACH2.

Authors
Dave, SS
MLA Citation
Dave, SS. "The polyphony of BACH2." Blood 123.7 (February 2014): 950-.
PMID
24526774
Source
epmc
Published In
Blood
Volume
123
Issue
7
Publish Date
2014
Start Page
950
DOI
10.1182/blood-2014-01-542449

Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma.

Merkel cell polyomavirus (MCPyV) is a DNA virus whose pathogenic mechanisms in Merkel cell carcinoma (MCC) are still being unraveled. Emerging reports of an association between MCPyV and chronic lymphocytic lymphoma (CLL) have begun to broaden our understanding of the oncogenic mechanisms of this virus and the known association between these 2 malignancies. Herein, we report a case of MCC demonstrating a B-cell immunophenotype arising in a patient with CLL being treated with rituximab. In this context, we discuss the differential diagnostic considerations, especially with cutaneous Richter transformation (diffuse large B-cell lymphoma). We also assessed for the presence of MCPyV in both the patient's MCC and the CLL. Finally, we provide a large meta-analysis of patients with CLL and MCC. Patients with both MCC and CLL have a dismal prognosis, with greater than 50% overall mortality within the first year and a half after MCC diagnosis.

Authors
Papalas, JA; McKinney, MS; Kulbacki, E; Dave, SS; Wang, E
MLA Citation
Papalas, JA, McKinney, MS, Kulbacki, E, Dave, SS, and Wang, E. "Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma." The American Journal of dermatopathology 36.2 (February 2014): 148-152.
PMID
24556900
Source
epmc
Published In
American Journal of Dermatopathology
Volume
36
Issue
2
Publish Date
2014
Start Page
148
End Page
152
DOI
10.1097/dad.0b013e31829ed784

Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex ® system

Authors
Collie, AMB; Nölling, J; Divakar, KM; Lin, JJ; Carver, P; Durkin, LM; Hill, BT; Smith, MR; Radivoyevitch, T; Kong, LI; Daly, T; Murugesan, G; Guenther-Johnson, J; Dave, SS; Manilich, EA; Hsi, ED
MLA Citation
Collie, AMB, Nölling, J, Divakar, KM, Lin, JJ, Carver, P, Durkin, LM, Hill, BT, Smith, MR, Radivoyevitch, T, Kong, LI, Daly, T, Murugesan, G, Guenther-Johnson, J, Dave, SS, Manilich, EA, and Hsi, ED. "Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex ® system." British Journal of Haematology 167.2 (January 1, 2014): 281-285. (Letter)
Source
scopus
Published In
British Journal of Haematology
Volume
167
Issue
2
Publish Date
2014
Start Page
281
End Page
285
DOI
10.1111/bjh.12983

Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and fewer than half of patients are cured with standard first-line therapy. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL, one of the most common cancers in veterinary oncology, is morphologically similar to hDLBCL and is treated using similar chemotherapeutic protocols. With genomic technologies, it is now possible to molecularly evaluate dogs as a potential large-animal model for hDLBCL. We evaluated canine B-cell lymphomas (cBCL) using immunohistochemistry (IHC) and gene expression profiling. cBCL expression profiles were similar in many ways to hDLBCLs. For instance, a subset had increased expression of NF-κB pathway genes, mirroring human activated B-cell (ABC)-type DLBCL. Furthermore, immunoglobulin heavy chain ongoing mutation status, which is correlated with ABC/germinal center B-cell cell of origin in hDLBCL, separated cBCL into two groups with statistically different progression-free and overall survival times. In contrast with hDLBCL, cBCL rarely expressed BCL6 and MUM1/IRF4 by IHC. Collectively, these studies identify molecular similarities to hDLBCL that introduce pet dogs as a representative model of hDLBCL for future studies, including therapeutic clinical trials.

Authors
Richards, KL; Motsinger-Reif, AA; Chen, H-W; Fedoriw, Y; Fan, C; Nielsen, DM; Small, GW; Thomas, R; Smith, C; Dave, SS; Perou, CM; Breen, M; Borst, LB; Suter, SE
MLA Citation
Richards, KL, Motsinger-Reif, AA, Chen, H-W, Fedoriw, Y, Fan, C, Nielsen, DM, Small, GW, Thomas, R, Smith, C, Dave, SS, Perou, CM, Breen, M, Borst, LB, and Suter, SE. "Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL." Cancer Res 73.16 (August 15, 2013): 5029-5039.
PMID
23783577
Source
pubmed
Published In
Cancer Research
Volume
73
Issue
16
Publish Date
2013
Start Page
5029
End Page
5039
DOI
10.1158/0008-5472.CAN-12-3546

PAK1 mediates resistance to PI3K inhibition in lymphomas.

PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas. EXPERIMENTAL DESIGN: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. RESULTS: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition. CONCLUSION: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

Authors
Walsh, K; McKinney, MS; Love, C; Liu, Q; Fan, A; Patel, A; Smith, J; Beaven, A; Jima, DD; Dave, SS
MLA Citation
Walsh, K, McKinney, MS, Love, C, Liu, Q, Fan, A, Patel, A, Smith, J, Beaven, A, Jima, DD, and Dave, SS. "PAK1 mediates resistance to PI3K inhibition in lymphomas." Clin Cancer Res 19.5 (March 1, 2013): 1106-1115.
PMID
23300274
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
5
Publish Date
2013
Start Page
1106
End Page
1115
DOI
10.1158/1078-0432.CCR-12-1060

Biomimetic, synthetic HDL nanostructures for lymphoma.

New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.

Authors
Yang, S; Damiano, MG; Zhang, H; Tripathy, S; Luthi, AJ; Rink, JS; Ugolkov, AV; Singh, ATK; Dave, SS; Gordon, LI; Thaxton, CS
MLA Citation
Yang, S, Damiano, MG, Zhang, H, Tripathy, S, Luthi, AJ, Rink, JS, Ugolkov, AV, Singh, ATK, Dave, SS, Gordon, LI, and Thaxton, CS. "Biomimetic, synthetic HDL nanostructures for lymphoma." Proc Natl Acad Sci U S A 110.7 (February 12, 2013): 2511-2516.
PMID
23345442
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
7
Publish Date
2013
Start Page
2511
End Page
2516
DOI
10.1073/pnas.1213657110

Genetic heterogeneity of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

Authors
Zhang, J; Grubor, V; Love, CL; Banerjee, A; Richards, KL; Mieczkowski, PA; Dunphy, C; Choi, W; Au, WY; Srivastava, G; Lugar, PL; Rizzieri, DA; Lagoo, AS; Bernal-Mizrachi, L; Mann, KP; Flowers, C; Naresh, K; Evens, A; Gordon, LI; Czader, M; Gill, JI; Hsi, ED; Liu, Q; Fan, A; Walsh, K; Jima, D; Smith, LL; Johnson, AJ; Byrd, JC; Luftig, MA; Ni, T; Zhu, J; Chadburn, A; Levy, S; Dunson, D; Dave, SS
MLA Citation
Zhang, J, Grubor, V, Love, CL, Banerjee, A, Richards, KL, Mieczkowski, PA, Dunphy, C, Choi, W, Au, WY, Srivastava, G, Lugar, PL, Rizzieri, DA, Lagoo, AS, Bernal-Mizrachi, L, Mann, KP, Flowers, C, Naresh, K, Evens, A, Gordon, LI, Czader, M, Gill, JI, Hsi, ED, Liu, Q, Fan, A, Walsh, K, Jima, D, Smith, LL, Johnson, AJ, Byrd, JC, Luftig, MA, Ni, T, Zhu, J, Chadburn, A, Levy, S, Dunson, D, and Dave, SS. "Genetic heterogeneity of diffuse large B-cell lymphoma." Proc Natl Acad Sci U S A 110.4 (January 22, 2013): 1398-1403.
PMID
23292937
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
4
Publish Date
2013
Start Page
1398
End Page
1403
DOI
10.1073/pnas.1205299110

Genomic stratification for the treatment of lymphomas.

The application of high-throughput genomic approaches in lymphomas has generated a wealth of data regarding the molecular underpinnings of these cancers. In this review, key findings from recent studies are discussed, as well as the genetic heterogeneity that underlies common lymphomas including diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia, and the implications for identifying new therapeutic opportunities and personalized medicine.

Authors
Dave, SS
MLA Citation
Dave, SS. "Genomic stratification for the treatment of lymphomas." Hematology Am Soc Hematol Educ Program 2013 (2013): 331-334. (Review)
PMID
24319200
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Volume
2013
Publish Date
2013
Start Page
331
End Page
334
DOI
10.1182/asheducation-2013.1.331

MicroRNA expression profiling using microarrays

MicroRNAs are small noncoding RNAs which are able to regulate gene expression at both the transcriptional and translational levels. There is a growing recognition of the role of microRNAs in nearly every tissue type and cellular process. Thus there is an increasing need for accurate quantitation of microRNA expression in a variety of tissues. Microarrays provide a robust method for the examination of microRNA expression. In this chapter, we describe detailed methods for the use of microarrays to measure microRNA expression and discuss methods for the analysis of microRNA expression data. © Springer Science+Business Media, New York 2013.

Authors
Love, C; Dave, S
MLA Citation
Love, C, and Dave, S. "MicroRNA expression profiling using microarrays." Methods in Molecular Biology 999 (2013): 285-296.
PMID
23666707
Source
scival
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
999
Publish Date
2013
Start Page
285
End Page
296
DOI
10.1007/978-1-62703-357-2-21

Lymphomas

Authors
Dave, S; Walsh, K
MLA Citation
Dave, S, and Walsh, K. "Lymphomas." Genomic and Personalized Medicine 2 (2013): 668-674.
Source
scival
Published In
Genomic and Personalized Medicine
Volume
2
Publish Date
2013
Start Page
668
End Page
674
DOI
10.1016/B978-0-12-382227-7.00057-4

The genetic landscape of mutations in Burkitt lymphoma.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.

Authors
Love, C; Sun, Z; Jima, D; Li, G; Zhang, J; Miles, R; Richards, KL; Dunphy, CH; Choi, WWL; Srivastava, G; Lugar, PL; Rizzieri, DA; Lagoo, AS; Bernal-Mizrachi, L; Mann, KP; Flowers, CR; Naresh, KN; Evens, AM; Chadburn, A; Gordon, LI; Czader, MB; Gill, JI; Hsi, ED; Greenough, A; Moffitt, AB; McKinney, M; Banerjee, A; Grubor, V; Levy, S; Dunson, DB; Dave, SS
MLA Citation
Love, C, Sun, Z, Jima, D, Li, G, Zhang, J, Miles, R, Richards, KL, Dunphy, CH, Choi, WWL, Srivastava, G, Lugar, PL, Rizzieri, DA, Lagoo, AS, Bernal-Mizrachi, L, Mann, KP, Flowers, CR, Naresh, KN, Evens, AM, Chadburn, A, Gordon, LI, Czader, MB, Gill, JI, Hsi, ED, Greenough, A, Moffitt, AB, McKinney, M, Banerjee, A, Grubor, V, Levy, S, Dunson, DB, and Dave, SS. "The genetic landscape of mutations in Burkitt lymphoma." Nat Genet 44.12 (December 2012): 1321-1325.
PMID
23143597
Source
pubmed
Published In
Nature Genetics
Volume
44
Issue
12
Publish Date
2012
Start Page
1321
End Page
1325
DOI
10.1038/ng.2468

Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation.

Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression to immortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changes following primary B-cell infection, both during initial proliferation and through transformation into lymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transition from resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAs changed uniquely from early proliferation through LCL outgrowth. We identified constitutively and dynamically EBV-regulated biological processes, protein classes, and targets of specific transcription factors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathway were highly enriched. However, the transition from early to long-term outgrowth was characterized by genes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-κB activity. It was previously thought that the major viral protein responsible for NF-κB activation, latent membrane protein 1 (LMP1), is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1 expression and NF-κB activity are not evident until 3 weeks after primary B-cell infection. Furthermore, heterologous NF-κB activation during the first week after infection increased the transformation efficiency, while early NF-κB inhibition had no effect on transformation. Rather, inhibition of NF-κB was not toxic to EBV-infected cells until LMP1 levels and NF-κB activity were high. These data collectively highlight the dynamic nature of EBV-regulated host gene expression and support the notion that early EBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from that of LCLs.

Authors
Price, AM; Tourigny, JP; Forte, E; Salinas, RE; Dave, SS; Luftig, MA
MLA Citation
Price, AM, Tourigny, JP, Forte, E, Salinas, RE, Dave, SS, and Luftig, MA. "Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation." J Virol 86.20 (October 2012): 11096-11106.
PMID
22855490
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
20
Publish Date
2012
Start Page
11096
End Page
11106
DOI
10.1128/JVI.01069-12

Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared. SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P(1), suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype.

Authors
Lugar, PL; Love, C; Grammer, AC; Dave, SS; Lipsky, PE
MLA Citation
Lugar, PL, Love, C, Grammer, AC, Dave, SS, and Lipsky, PE. "Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus." PLoS One 7.9 (2012): e44362-.
PMID
23028528
Source
pubmed
Published In
PloS one
Volume
7
Issue
9
Publish Date
2012
Start Page
e44362
DOI
10.1371/journal.pone.0044362

The Epstein-Barr virus (EBV)-induced tumor suppressor microrna MiR-34a is growth promoting in EBV-infected B cells

Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts. © 2012, American Society for Microbiology.

Authors
Forte, E; Salinas, RE; Chang, C; Zhou, T; Linnstaedt, SD; Gottwein, E; Jacobs, C; Jima, D; Li, Q-J; Dave, SS; Luftig, MA
MLA Citation
Forte, E, Salinas, RE, Chang, C, Zhou, T, Linnstaedt, SD, Gottwein, E, Jacobs, C, Jima, D, Li, Q-J, Dave, SS, and Luftig, MA. "The Epstein-Barr virus (EBV)-induced tumor suppressor microrna MiR-34a is growth promoting in EBV-infected B cells." Journal of Virology 86.12 (2012): 6889-6898.
PMID
22496226
Source
scival
Published In
Journal of virology
Volume
86
Issue
12
Publish Date
2012
Start Page
6889
End Page
6898
DOI
10.1128/JVI.07056-11

Burkitt lymphoma: Analysis of the genome

Authors
Dave, S; O'Brien, S
MLA Citation
Dave, S, and O'Brien, S. "Burkitt lymphoma: Analysis of the genome." Clinical Advances in Hematology and Oncology 10.1 (2012): 54-55.
PMID
22398809
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
10
Issue
1
Publish Date
2012
Start Page
54
End Page
55

Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines.

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in latency and lymphomagenesis. Using PAR-CLIP, a technology which allows the direct and transcriptome-wide identification of miRNA targets, we delineate the target sites for all viral and cellular miRNAs expressed in PEL cell lines. The resulting data set revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs, including many involved in pathways relevant to KSHV pathogenesis. Moreover, 58% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of cellular miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, this study identifies an extensive list of KSHV miRNA targets, which are likely to influence viral replication and pathogenesis.

Authors
Gottwein, E; Corcoran, DL; Mukherjee, N; Skalsky, RL; Hafner, M; Nusbaum, JD; Shamulailatpam, P; Love, CL; Dave, SS; Tuschl, T; Ohler, U; Cullen, BR
MLA Citation
Gottwein, E, Corcoran, DL, Mukherjee, N, Skalsky, RL, Hafner, M, Nusbaum, JD, Shamulailatpam, P, Love, CL, Dave, SS, Tuschl, T, Ohler, U, and Cullen, BR. "Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines." Cell Host Microbe 10.5 (November 17, 2011): 515-526.
PMID
22100165
Source
pubmed
Published In
Cell Host and Microbe
Volume
10
Issue
5
Publish Date
2011
Start Page
515
End Page
526
DOI
10.1016/j.chom.2011.09.012

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Authors
Lanasa, MC; Allgood, SD; Slager, SL; Dave, SS; Love, C; Marti, GE; Kay, NE; Hanson, CA; Rabe, KG; Achenbach, SJ; Goldin, LR; Camp, NJ; Goodman, BK; Vachon, CM; Spector, LG; Rassenti, LZ; Leis, JF; Gockerman, JP; Strom, SS; Call, TG; Glenn, M; Cerhan, JR; Levesque, MC; Weinberg, JB; Caporaso, NE
MLA Citation
Lanasa, MC, Allgood, SD, Slager, SL, Dave, SS, Love, C, Marti, GE, Kay, NE, Hanson, CA, Rabe, KG, Achenbach, SJ, Goldin, LR, Camp, NJ, Goodman, BK, Vachon, CM, Spector, LG, Rassenti, LZ, Leis, JF, Gockerman, JP, Strom, SS, Call, TG, Glenn, M, Cerhan, JR, Levesque, MC, Weinberg, JB, and Caporaso, NE. "Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL." Leukemia 25.9 (September 2011): 1459-1466.
PMID
21617698
Source
pubmed
Published In
Leukemia
Volume
25
Issue
9
Publish Date
2011
Start Page
1459
End Page
1466
DOI
10.1038/leu.2011.117

HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.

HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers.

Authors
Hartman, ZC; Yang, X-Y; Glass, O; Lei, G; Osada, T; Dave, SS; Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Hartman, ZC, Yang, X-Y, Glass, O, Lei, G, Osada, T, Dave, SS, Morse, MA, Clay, TM, and Lyerly, HK. "HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis." Cancer Res 71.13 (July 1, 2011): 4380-4391.
PMID
21518778
Source
pubmed
Published In
Cancer Research
Volume
71
Issue
13
Publish Date
2011
Start Page
4380
End Page
4391
DOI
10.1158/0008-5472.CAN-11-0308

Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component

The normal counterparts of mantle cell lymphoma (MCL) are naive, quiescent B cells that have not been processed through the germinal center (GC). For this reason, although lymphomas arising from GC or post-GC B cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from 6 centers and were studied by immunohistochemistry, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms analysis, capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis of microdissections of each of the MCL and PC populations to assess their clonal relationship. The clinical presentation was rather unusual compared with typical MCL, with 2 cases arising from the extranodal soft tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases, the PC population was clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic population. The 2 cases with clonal diversity denoted the coexistence of 2 different tumors in a composite lymphoma/PC neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor. Copyright © 2011 by Lippincott Williams & Wilkins.

Authors
Visco, C; Hoeller, S; Malik, JT; Xu-Monette, ZY; Wiggins, ML; Liu, J; Sanger, WG; Liu, Z; Chang, J; Ranheim, EA; Gradowski, JF; Serrano, S; Wang, H-Y; Liu, Q; Dave, S; Olsen, B; Gascoyne, RD; Campo, E; Swerdlow, SH; Chan, WC; Tzankov, A; Young, KH
MLA Citation
Visco, C, Hoeller, S, Malik, JT, Xu-Monette, ZY, Wiggins, ML, Liu, J, Sanger, WG, Liu, Z, Chang, J, Ranheim, EA, Gradowski, JF, Serrano, S, Wang, H-Y, Liu, Q, Dave, S, Olsen, B, Gascoyne, RD, Campo, E, Swerdlow, SH, Chan, WC, Tzankov, A, and Young, KH. "Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component." American Journal of Surgical Pathology 35.2 (2011): 177-189.
PMID
21263238
Source
scival
Published In
American Journal of Surgical Pathology
Volume
35
Issue
2
Publish Date
2011
Start Page
177
End Page
189
DOI
10.1097/PAS.0b013e3182049a9c

An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.

Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization.

Authors
Nikitin, PA; Yan, CM; Forte, E; Bocedi, A; Tourigny, JP; White, RE; Allday, MJ; Patel, A; Dave, SS; Kim, W; Hu, K; Guo, J; Tainter, D; Rusyn, E; Luftig, MA
MLA Citation
Nikitin, PA, Yan, CM, Forte, E, Bocedi, A, Tourigny, JP, White, RE, Allday, MJ, Patel, A, Dave, SS, Kim, W, Hu, K, Guo, J, Tainter, D, Rusyn, E, and Luftig, MA. "An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells." Cell Host Microbe 8.6 (December 16, 2010): 510-522.
PMID
21147465
Source
pubmed
Published In
Cell Host and Microbe
Volume
8
Issue
6
Publish Date
2010
Start Page
510
End Page
522
DOI
10.1016/j.chom.2010.11.004

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Authors
Jima, DD; Zhang, J; Jacobs, C; Richards, KL; Dunphy, CH; Choi, WWL; Au, WY; Srivastava, G; Czader, MB; Rizzieri, DA; Lagoo, AS; Lugar, PL; Mann, KP; Flowers, CR; Bernal-Mizrachi, L; Naresh, KN; Evens, AM; Gordon, LI; Luftig, M; Friedman, DR; Weinberg, JB; Thompson, MA; Gill, JI; Liu, Q; How, T; Grubor, V; Gao, Y; Patel, A; Wu, H; Zhu, J; Blobe, GC; Lipsky, PE; Chadburn, A; Dave, SS; Hematologic Malignancies Research Consortium,
MLA Citation
Jima, DD, Zhang, J, Jacobs, C, Richards, KL, Dunphy, CH, Choi, WWL, Au, WY, Srivastava, G, Czader, MB, Rizzieri, DA, Lagoo, AS, Lugar, PL, Mann, KP, Flowers, CR, Bernal-Mizrachi, L, Naresh, KN, Evens, AM, Gordon, LI, Luftig, M, Friedman, DR, Weinberg, JB, Thompson, MA, Gill, JI, Liu, Q, How, T, Grubor, V, Gao, Y, Patel, A, Wu, H, Zhu, J, Blobe, GC, Lipsky, PE, Chadburn, A, Dave, SS, and Hematologic Malignancies Research Consortium, . "Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs." Blood 116.23 (December 2, 2010): e118-e127.
PMID
20733160
Source
pubmed
Published In
Blood
Volume
116
Issue
23
Publish Date
2010
Start Page
e118
End Page
e127
DOI
10.1182/blood-2010-05-285403

Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling.

The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.

Authors
Hartmann, EM; Campo, E; Wright, G; Lenz, G; Salaverria, I; Jares, P; Xiao, W; Braziel, RM; Rimsza, LM; Chan, W-C; Weisenburger, DD; Delabie, J; Jaffe, ES; Gascoyne, RD; Dave, SS; Mueller-Hermelink, H-K; Staudt, LM; Ott, G; Beà, S; Rosenwald, A
MLA Citation
Hartmann, EM, Campo, E, Wright, G, Lenz, G, Salaverria, I, Jares, P, Xiao, W, Braziel, RM, Rimsza, LM, Chan, W-C, Weisenburger, DD, Delabie, J, Jaffe, ES, Gascoyne, RD, Dave, SS, Mueller-Hermelink, H-K, Staudt, LM, Ott, G, Beà, S, and Rosenwald, A. "Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling." Blood 116.6 (August 12, 2010): 953-961.
PMID
20421449
Source
pubmed
Published In
Blood
Volume
116
Issue
6
Publish Date
2010
Start Page
953
End Page
961
DOI
10.1182/blood-2010-01-263806

Host factors for risk and survival in lymphoma.

All cancers arise from complex interactions between aspects of the patient (host) biology and the environment. Once tumors arise, they frequently remain dependent on interactions with their microenvironment for their growth and proliferation. In this review, we examine the contributions of the host genetics and environmental exposures to the development of lymphoma. We will further examine the interactions of the tumor and the microenvironment that influence tumor growth and proliferation.

Authors
Dave, SS
MLA Citation
Dave, SS. "Host factors for risk and survival in lymphoma." Hematology Am Soc Hematol Educ Program 2010 (2010): 255-258. (Review)
PMID
21239802
Source
pubmed
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Volume
2010
Publish Date
2010
Start Page
255
End Page
258
DOI
10.1182/asheducation-2010.1.255

Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-kappaB through blocking IkappaBalpha degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.ClinicalTrials.gov under identifier NCT00057902.

Authors
Dunleavy, K; Pittaluga, S; Czuczman, MS; Dave, SS; Wright, G; Grant, N; Shovlin, M; Jaffe, ES; Janik, JE; Staudt, LM; Wilson, WH
MLA Citation
Dunleavy, K, Pittaluga, S, Czuczman, MS, Dave, SS, Wright, G, Grant, N, Shovlin, M, Jaffe, ES, Janik, JE, Staudt, LM, and Wilson, WH. "Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma." Blood 113.24 (June 11, 2009): 6069-6076.
PMID
19380866
Source
pubmed
Published In
Blood
Volume
113
Issue
24
Publish Date
2009
Start Page
6069
End Page
6076
DOI
10.1182/blood-2009-01-199679

Patterns of microRNA expression characterize stages of human B-cell differentiation.

Mature B-cell differentiation provides an important mechanism for the acquisition of adaptive immunity. Malignancies derived from mature B cells constitute the majority of leukemias and lymphomas. These malignancies often maintain the characteristics of the normal B cells that they are derived from, a feature that is frequently used in their diagnosis. The role of microRNAs in mature B cells is largely unknown. Through concomitant microRNA and mRNA profiling, we demonstrate a potential regulatory role for microRNAs at every stage of the mature B-cell differentiation process. In addition, we have experimentally identified a direct role for the microRNA regulation of key transcription factors in B-cell differentiation: LMO2 and PRDM1 (Blimp1). We also profiled the microRNA of B-cell tumors derived from diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia. We found that, in contrast to many other malignancies, common B-cell malignancies do not down-regulate microRNA expression. Although these tumors could be distinguished from each other with use of microRNA expression, each tumor type maintained the expression of the lineage-specific microRNAs. Expression of these lineage-specific microRNAs could correctly predict the lineage of B-cell malignancies in more than 95% of the cases. Thus, our data demonstrate that microRNAs may be important in maintaining the mature B-cell phenotype in normal and malignant B cells.

Authors
Zhang, J; Jima, DD; Jacobs, C; Fischer, R; Gottwein, E; Huang, G; Lugar, PL; Lagoo, AS; Rizzieri, DA; Friedman, DR; Weinberg, JB; Lipsky, PE; Dave, SS
MLA Citation
Zhang, J, Jima, DD, Jacobs, C, Fischer, R, Gottwein, E, Huang, G, Lugar, PL, Lagoo, AS, Rizzieri, DA, Friedman, DR, Weinberg, JB, Lipsky, PE, and Dave, SS. "Patterns of microRNA expression characterize stages of human B-cell differentiation." Blood 113.19 (May 7, 2009): 4586-4594.
PMID
19202128
Source
pubmed
Published In
Blood
Volume
113
Issue
19
Publish Date
2009
Start Page
4586
End Page
4594
DOI
10.1182/blood-2008-09-178186

Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.

Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

Authors
Longo, NS; Lugar, PL; Yavuz, S; Zhang, W; Krijger, PHL; Russ, DE; Jima, DD; Dave, SS; Grammer, AC; Lipsky, PE
MLA Citation
Longo, NS, Lugar, PL, Yavuz, S, Zhang, W, Krijger, PHL, Russ, DE, Jima, DD, Dave, SS, Grammer, AC, and Lipsky, PE. "Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting." Blood 113.16 (April 16, 2009): 3706-3715.
PMID
19023113
Source
pubmed
Published In
Blood
Volume
113
Issue
16
Publish Date
2009
Start Page
3706
End Page
3715
DOI
10.1182/blood-2008-10-183632

SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype

Background: Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. Design and Methods: The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. Results: SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt's lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt's lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. Conclusions: SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma. ©2009 Ferrata Storti Foundation.

Authors
Mozos, A; Royo, C; Hartmann, E; Jong, DD; Baró, C; Valera, A; Fu, K; Weisenburger, DD; Delabie, J; Chuang, S-S; Jaffe, ES; Ruiz-Marcellan, C; Dave, S; Rimsza, L; Braziel, R; Gascoyne, RD; Solé, F; López-Guillermo, A; Colomer, D; Staudt, LM; Rosenwald, A; Ott, G; Jares, P; Campo, E
MLA Citation
Mozos, A, Royo, C, Hartmann, E, Jong, DD, Baró, C, Valera, A, Fu, K, Weisenburger, DD, Delabie, J, Chuang, S-S, Jaffe, ES, Ruiz-Marcellan, C, Dave, S, Rimsza, L, Braziel, R, Gascoyne, RD, Solé, F, López-Guillermo, A, Colomer, D, Staudt, LM, Rosenwald, A, Ott, G, Jares, P, and Campo, E. "SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype." Haematologica 94.11 (2009): 1555-1562.
PMID
19880778
Source
scival
Published In
Haematologica
Volume
94
Issue
11
Publish Date
2009
Start Page
1555
End Page
1562
DOI
10.3324/haematol.2009.010264

Stromal gene signatures in large-B-cell lymphomas.

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Authors
Lenz, G; Wright, G; Dave, SS; Xiao, W; Powell, J; Zhao, H; Xu, W; Tan, B; Goldschmidt, N; Iqbal, J; Vose, J; Bast, M; Fu, K; Weisenburger, DD; Greiner, TC; Armitage, JO; Kyle, A; May, L; Gascoyne, RD; Connors, JM; Troen, G; Holte, H; Kvaloy, S; Dierickx, D; Verhoef, G; Delabie, J; Smeland, EB; Jares, P; Martinez, A; Lopez-Guillermo, A; Montserrat, E; Campo, E; Braziel, RM; Miller, TP; Rimsza, LM; Cook, JR; Pohlman, B; Sweetenham, J; Tubbs, RR; Fisher, RI; Hartmann, E; Rosenwald, A; Ott, G et al.
MLA Citation
Lenz, G, Wright, G, Dave, SS, Xiao, W, Powell, J, Zhao, H, Xu, W, Tan, B, Goldschmidt, N, Iqbal, J, Vose, J, Bast, M, Fu, K, Weisenburger, DD, Greiner, TC, Armitage, JO, Kyle, A, May, L, Gascoyne, RD, Connors, JM, Troen, G, Holte, H, Kvaloy, S, Dierickx, D, Verhoef, G, Delabie, J, Smeland, EB, Jares, P, Martinez, A, Lopez-Guillermo, A, Montserrat, E, Campo, E, Braziel, RM, Miller, TP, Rimsza, LM, Cook, JR, Pohlman, B, Sweetenham, J, Tubbs, RR, Fisher, RI, Hartmann, E, Rosenwald, A, and Ott, G et al. "Stromal gene signatures in large-B-cell lymphomas." N Engl J Med 359.22 (November 27, 2008): 2313-2323.
PMID
19038878
Source
pubmed
Published In
The New England journal of medicine
Volume
359
Issue
22
Publish Date
2008
Start Page
2313
End Page
2323
DOI
10.1056/NEJMoa0802885

Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.

Authors
Lenz, G; Wright, GW; Emre, NCT; Kohlhammer, H; Dave, SS; Davis, RE; Carty, S; Lam, LT; Shaffer, AL; Xiao, W; Powell, J; Rosenwald, A; Ott, G; Muller-Hermelink, HK; Gascoyne, RD; Connors, JM; Campo, E; Jaffe, ES; Delabie, J; Smeland, EB; Rimsza, LM; Fisher, RI; Weisenburger, DD; Chan, WC; Staudt, LM
MLA Citation
Lenz, G, Wright, GW, Emre, NCT, Kohlhammer, H, Dave, SS, Davis, RE, Carty, S, Lam, LT, Shaffer, AL, Xiao, W, Powell, J, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Gascoyne, RD, Connors, JM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Rimsza, LM, Fisher, RI, Weisenburger, DD, Chan, WC, and Staudt, LM. "Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways." Proc Natl Acad Sci U S A 105.36 (September 9, 2008): 13520-13525.
PMID
18765795
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
36
Publish Date
2008
Start Page
13520
End Page
13525
DOI
10.1073/pnas.0804295105

Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma.

BACKGROUND: Burkitt's lymphoma is an aggressive B-cell lymphoma characterized by typical morphological, immunophenotypic and molecular features. Gene expression profiling provided a molecular signature of Burkitt's lymphoma, but also demonstrated that a subset of aggressive B-cell lymphomas not fulfilling the current World Health Organization criteria for the diagnosis of Burkitt's lymphoma nonetheless show a molecular signature of Burkitt's lymphoma ('discrepant Burkitt's lymphoma'). Given the different treatment of Burkitt's lymphoma and diffuse large B-cell lymphomas we investigated molecular differences within gene expression-defined Burkitt's lymphoma. DESIGN AND METHODS: We studied tumors from 51 Burkitt's lymphoma patients, comprising 26 with classic Burkitt's lymphoma, 17 with atypical Burkitt's lymphoma and 8 with 'discrepant Burkitt's lymphoma', by comparative genomic hybridization and gene expression profiling. RESULTS: Classic and atypical Burkitt's lymphoma (excluding 'discrepant Burkitt's lymphoma'), in adult and pediatric cases do not differ in underlying genomic imbalances or gene expression suggesting that these subgroups are molecularly homogeneous. 'Discrepant Burkitt's lymphoma', however, differ dramatically in the absolute number of alterations from classic/atypical Burkitt's lymphoma and from diffuse large B-cell lymphoma. Moreover, this category includes lymphomas that carry both the t(14;18) and t(8;14) translocations and are clinically characterized by presentation in adult patients and an aggressive course. CONCLUSIONS: Pediatric and adult Burkitt's lymphoma are molecularly homogeneous, whereas 'discrepant Burkitt's lymphoma' differ in underlying genetic and clinical features from typical/atypical Burkitt's lymphoma. 'Discrepant Burkitt's lymphoma' may therefore form a distinct genetic subgroup of aggressive B-cell lymphomas, which show poor response to multi-agent chemotherapy.

Authors
Salaverria, I; Zettl, A; Beà, S; Hartmann, EM; Dave, SS; Wright, GW; Boerma, E-J; Kluin, PM; Ott, G; Chan, WC; Weisenburger, DD; Lopez-Guillermo, A; Gascoyne, RD; Delabie, J; Rimsza, LM; Braziel, RM; Jaffe, ES; Staudt, LM; Müller-Hermelink, HK; Campo, E; Rosenwald, A; Leukemia and Lymphoma Molecular Profiling Project (LLMPP),
MLA Citation
Salaverria, I, Zettl, A, Beà, S, Hartmann, EM, Dave, SS, Wright, GW, Boerma, E-J, Kluin, PM, Ott, G, Chan, WC, Weisenburger, DD, Lopez-Guillermo, A, Gascoyne, RD, Delabie, J, Rimsza, LM, Braziel, RM, Jaffe, ES, Staudt, LM, Müller-Hermelink, HK, Campo, E, Rosenwald, A, and Leukemia and Lymphoma Molecular Profiling Project (LLMPP), . "Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma." Haematologica 93.9 (September 2008): 1327-1334.
PMID
18698080
Source
pubmed
Published In
Haematologica
Volume
93
Issue
9
Publish Date
2008
Start Page
1327
End Page
1334
DOI
10.3324/haematol.13071

Follicular lymphoma and the microenvironment.

Authors
Dave, SS
MLA Citation
Dave, SS. "Follicular lymphoma and the microenvironment." Blood 111.9 (May 1, 2008): 4427-4428.
PMID
18441242
Source
pubmed
Published In
Blood
Volume
111
Issue
9
Publish Date
2008
Start Page
4427
End Page
4428
DOI
10.1182/blood-2008-01-134643

Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. In the least curable (ABC) subtype of DLBCL, survival of the malignant cells is dependent on constitutive activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway. In normal B cells, antigen receptor-induced NF-kappaB activation requires CARD11, a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, we sequenced the CARD11 gene in human DLBCL tumors. We detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappaB activation and enhanced NF-kappaB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogenein DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.

Authors
Lenz, G; Davis, RE; Ngo, VN; Lam, L; George, TC; Wright, GW; Dave, SS; Zhao, H; Xu, W; Rosenwald, A; Ott, G; Muller-Hermelink, HK; Gascoyne, RD; Connors, JM; Rimsza, LM; Campo, E; Jaffe, ES; Delabie, J; Smeland, EB; Fisher, RI; Chan, WC; Staudt, LM
MLA Citation
Lenz, G, Davis, RE, Ngo, VN, Lam, L, George, TC, Wright, GW, Dave, SS, Zhao, H, Xu, W, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Gascoyne, RD, Connors, JM, Rimsza, LM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Fisher, RI, Chan, WC, and Staudt, LM. "Oncogenic CARD11 mutations in human diffuse large B cell lymphoma." Science 319.5870 (March 21, 2008): 1676-1679.
PMID
18323416
Source
pubmed
Published In
Science
Volume
319
Issue
5870
Publish Date
2008
Start Page
1676
End Page
1679
DOI
10.1126/science.1153629

IRF4 addiction in multiple myeloma

The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells. ©2008 Macmillan Publishers Limited. All rights reserved.

Authors
Shaffer, AL; Emre, NCT; Lamy, L; Ngo, VN; Wright, G; Xiao, W; Powell, J; Dave, S; Yu, X; Zhao, H; Zeng, Y; Chen, B; Epstein, J; Staudt, LM
MLA Citation
Shaffer, AL, Emre, NCT, Lamy, L, Ngo, VN, Wright, G, Xiao, W, Powell, J, Dave, S, Yu, X, Zhao, H, Zeng, Y, Chen, B, Epstein, J, and Staudt, LM. "IRF4 addiction in multiple myeloma." Nature 454.7201 (2008): 226-231.
PMID
18568025
Source
scival
Published In
Nature
Volume
454
Issue
7201
Publish Date
2008
Start Page
226
End Page
231
DOI
10.1038/nature07064

Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas.

PURPOSE: Nodal peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous group of neoplasms, suggesting the existence of molecular differences contributing to their histologic and clinical variability. Initial expression profiling studies of T-cell lymphomas have been inconclusive in yielding clinically relevant insights. We applied DNA microarrays to gain insight into the molecular signatures associated with prognosis. MATERIALS AND METHODS: We analyzed the expression profiles of 35 nodal PTCLs (23 PTCLs unspecified and 12 angioimmunoblastic) using two different microarray platforms, the cDNA microarray developed at the Spanish National Cancer Centre and an oligonucleotide microarray. RESULTS: We identified five clusters of genes, the expression of which varied significantly among the samples. Genes in these clusters seemed to be functionally related to different cellular processes such as proliferation, inflammatory response, and T-cell or B-cell lineages. Regardless of the microarray platform used, overexpression of genes in the proliferation signature was associated significantly with shorter survival of patients. This proliferation signature included genes commonly associated with the cell cycle, such as CCNA, CCNB, TOP2A, and PCNA. Moreover the PTCL proliferation signature showed a statistically significant inverse correlation with clusters of the inflammatory response (P < .0001), as well as with the percentage of CD68(+) cells. CONCLUSION: Our findings indicate that proliferation could be an important factor in evaluating nodal PTCL outcome and may help to define a more aggressive phenotype.

Authors
Cuadros, M; Dave, SS; Jaffe, ES; Honrado, E; Milne, R; Alves, J; Rodríguez, J; Zajac, M; Benitez, J; Staudt, LM; Martinez-Delgado, B
MLA Citation
Cuadros, M, Dave, SS, Jaffe, ES, Honrado, E, Milne, R, Alves, J, Rodríguez, J, Zajac, M, Benitez, J, Staudt, LM, and Martinez-Delgado, B. "Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas." J Clin Oncol 25.22 (August 1, 2007): 3321-3329.
PMID
17577022
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
22
Publish Date
2007
Start Page
3321
End Page
3329
DOI
10.1200/JCO.2006.09.4474

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.

Authors
Lenz, G; Nagel, I; Siebert, R; Roschke, AV; Sanger, W; Wright, GW; Dave, SS; Tan, B; Zhao, H; Rosenwald, A; Muller-Hermelink, HK; Gascoyne, RD; Campo, E; Jaffe, ES; Smeland, EB; Fisher, RI; Kuehl, WM; Chan, WC; Staudt, LM
MLA Citation
Lenz, G, Nagel, I, Siebert, R, Roschke, AV, Sanger, W, Wright, GW, Dave, SS, Tan, B, Zhao, H, Rosenwald, A, Muller-Hermelink, HK, Gascoyne, RD, Campo, E, Jaffe, ES, Smeland, EB, Fisher, RI, Kuehl, WM, Chan, WC, and Staudt, LM. "Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma." J Exp Med 204.3 (March 19, 2007): 633-643.
PMID
17353367
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
204
Issue
3
Publish Date
2007
Start Page
633
End Page
643
DOI
10.1084/jem.20062041

In reply [2]

Authors
Cuadros, M; Honrado, E; Zajac, M; Benitez, J; Martinez-Delgado, B; Dave, SS; Staudt, LM; Jaffe, ES; Milne, R; Alves, J; Rodríguez, J
MLA Citation
Cuadros, M, Honrado, E, Zajac, M, Benitez, J, Martinez-Delgado, B, Dave, SS, Staudt, LM, Jaffe, ES, Milne, R, Alves, J, and Rodríguez, J. "In reply [2]." Journal of Clinical Oncology 25.30 (2007): 4851-4852.
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4851
End Page
4852
DOI
10.1200/JCO.2007.13.4858

Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Mechanisms of constitutive NF-κB signaling in multiple myeloma are unknown. An inhibitor of IκB kinase β (IKKβ) targeting the classical NF-κB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-κB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-κB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-κB pathway is frequent in myeloma and suggest that IKKβ inhibitors hold promise for the treatment of this disease. © 2007 Elsevier Inc. All rights reserved.

Authors
Annunziata, CM; Davis, RE; Demchenko, Y; Bellamy, W; Gabrea, A; Zhan, F; Lenz, G; Hanamura, I; Wright, G; Xiao, W; Dave, S; Hurt, EM; Tan, B; Zhao, H; Stephens, O; Santra, M; Williams, DR; Dang, L; Barlogie, B; Jr, JDS; Kuehl, WM; Staudt, LM
MLA Citation
Annunziata, CM, Davis, RE, Demchenko, Y, Bellamy, W, Gabrea, A, Zhan, F, Lenz, G, Hanamura, I, Wright, G, Xiao, W, Dave, S, Hurt, EM, Tan, B, Zhao, H, Stephens, O, Santra, M, Williams, DR, Dang, L, Barlogie, B, Jr, JDS, Kuehl, WM, and Staudt, LM. "Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma." Cancer Cell 12.2 (2007): 115-130.
PMID
17692804
Source
scival
Published In
Cancer Cell
Volume
12
Issue
2
Publish Date
2007
Start Page
115
End Page
130
DOI
10.1016/j.ccr.2007.07.004

Gene expression signatures and outcome prediction in mature B-cell malignancies.

Non-Hodgkin's lymphomas comprise a diverse group of diseases that are subclassified by the state of differentiation of the malignant B cells, presence of specific cytogenetic abnormalities, and characteristic morphology. Gene expression profiling has revealed that within each category of non-Hodgkin's lymphoma, there exists a significant molecular heterogeneity that can be reflected in differences in tumor behavior and patient outcome. Appreciation of gene expression signatures that are associated with patient outcome will allow better prognostication of disease course and aid the application of molecularly selective patients to improve patient outcome.

Authors
Dave, SS
MLA Citation
Dave, SS. "Gene expression signatures and outcome prediction in mature B-cell malignancies." Curr Treat Options Oncol 7.4 (July 2006): 261-269. (Review)
PMID
16916486
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
7
Issue
4
Publish Date
2006
Start Page
261
End Page
269

Molecular diagnosis of Burkitt's lymphoma.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt's lymphoma. Burkitt's lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt's lymphoma, suggesting they represent cases of Burkitt's lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt's lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Authors
Dave, SS; Fu, K; Wright, GW; Lam, LT; Kluin, P; Boerma, E-J; Greiner, TC; Weisenburger, DD; Rosenwald, A; Ott, G; Müller-Hermelink, H-K; Gascoyne, RD; Delabie, J; Rimsza, LM; Braziel, RM; Grogan, TM; Campo, E; Jaffe, ES; Dave, BJ; Sanger, W; Bast, M; Vose, JM; Armitage, JO; Connors, JM; Smeland, EB; Kvaloy, S; Holte, H; Fisher, RI; Miller, TP; Montserrat, E; Wilson, WH; Bahl, M; Zhao, H; Yang, L; Powell, J; Simon, R; Chan, WC; Staudt, LM; Lymphoma/Leukemia Molecular Profiling Project,
MLA Citation
Dave, SS, Fu, K, Wright, GW, Lam, LT, Kluin, P, Boerma, E-J, Greiner, TC, Weisenburger, DD, Rosenwald, A, Ott, G, Müller-Hermelink, H-K, Gascoyne, RD, Delabie, J, Rimsza, LM, Braziel, RM, Grogan, TM, Campo, E, Jaffe, ES, Dave, BJ, Sanger, W, Bast, M, Vose, JM, Armitage, JO, Connors, JM, Smeland, EB, Kvaloy, S, Holte, H, Fisher, RI, Miller, TP, Montserrat, E, Wilson, WH, Bahl, M, Zhao, H, Yang, L, Powell, J, Simon, R, Chan, WC, Staudt, LM, and Lymphoma/Leukemia Molecular Profiling Project, . "Molecular diagnosis of Burkitt's lymphoma." N Engl J Med 354.23 (June 8, 2006): 2431-2442.
PMID
16760443
Source
pubmed
Published In
The New England journal of medicine
Volume
354
Issue
23
Publish Date
2006
Start Page
2431
End Page
2442
DOI
10.1056/NEJMoa055759

Drs. Dave and Staudt reply [5]

Authors
Dave, SS; Staudt, LM
MLA Citation
Dave, SS, and Staudt, LM. "Drs. Dave and Staudt reply [5]." New England Journal of Medicine 355.10 (2006): 1064--.
Source
scival
Published In
The New England journal of medicine
Volume
355
Issue
10
Publish Date
2006
Start Page
1064-
DOI
10.1056/NEJMc061833

A loss-of-function RNA interference screen for molecular targets in cancer

The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis1; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-κB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IκB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes. © 2006 Nature Publishing Group.

Authors
Ngo, VN; Davis, RE; Lamy, L; Yu, X; Zhao, H; Lenz, G; Lam, LT; Dave, S; Yang, L; Powell, J; Staudt, LM
MLA Citation
Ngo, VN, Davis, RE, Lamy, L, Yu, X, Zhao, H, Lenz, G, Lam, LT, Dave, S, Yang, L, Powell, J, and Staudt, LM. "A loss-of-function RNA interference screen for molecular targets in cancer." Nature 441.1 (2006): 106-110.
PMID
16572121
Source
scival
Published In
Nature
Volume
441
Issue
1
Publish Date
2006
Start Page
106
End Page
110
DOI
10.1038/nature04687

Gene expression profiling and outcome prediction in non-Hodgkin lymphoma

Gene expression profiling with microarrays has provided new insights into the molecular biology of tumors can that underlie differences in responses to therapy and patient outcomes. In diffuse large B-cell lymphoma, gene expression profiling has revealed at least 2 diseases that are strikingly different in their response to chemotherapy and the inhibition of critical oncogenic pathways. In follicular lymphoma, gene expression profiling showed that the host immune response to tumors is an important determinant of outcome and can strongly predict survival at the time of diagnosis. The application of immunologic therapies that modify the host immune response could have a major effect on survival in patients with follicular lymphoma. Thus, the application of gene expression profiling in non-Hodgkin lymphoma provides important prognostic information at the time of diagnosis and can be translated into therapeutic options that improve patient outcomes. © 2006 American Society for Blood and Marrow Transplantation.

Authors
Dave, S
MLA Citation
Dave, S. "Gene expression profiling and outcome prediction in non-Hodgkin lymphoma." Biology of Blood and Marrow Transplantation 12.SUPPL. 1 (2006): 50-52.
PMID
16399585
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
SUPPL. 1
Publish Date
2006
Start Page
50
End Page
52
DOI
10.1016/j.bbmt.2005.10.017

Immune signatures in follicular lymphoma [6] (multiple letters)

Authors
Tibshirani, R; Hong, W-J; Warnke, R; Chu, G; Staudt, LM; Wright, G; Dave, S
MLA Citation
Tibshirani, R, Hong, W-J, Warnke, R, Chu, G, Staudt, LM, Wright, G, and Dave, S. "Immune signatures in follicular lymphoma [6] (multiple letters)." New England Journal of Medicine 352.14 (2005): 1496-1497.
PMID
15818776
Source
scival
Published In
New England Journal of Medicine
Volume
352
Issue
14
Publish Date
2005
Start Page
1496
End Page
1497
DOI
10.1056/NEJM200504073521422

Cyclin D1-negative mantle cell lymphoma: A clinicopathologic study based on gene expression profiling

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL. © 2005 by The American Society of Hematology.

Authors
Fu, K; Weisenburger, DD; Greiner, TC; Dave, S; Wright, G; Rosenwald, A; Chiorazzi, M; Iqbal, J; Gesk, S; Siebert, R; Jong, DD; Jaffe, ES; Wilson, WH; Delabie, J; Ott, G; Dave, BJ; Sanger, WG; Smith, LM; Rimsza, L; Braziel, RM; Müller-Hermelink, HK; Campo, E; Gascoyne, RD; Staudt, LM; Chan, WC
MLA Citation
Fu, K, Weisenburger, DD, Greiner, TC, Dave, S, Wright, G, Rosenwald, A, Chiorazzi, M, Iqbal, J, Gesk, S, Siebert, R, Jong, DD, Jaffe, ES, Wilson, WH, Delabie, J, Ott, G, Dave, BJ, Sanger, WG, Smith, LM, Rimsza, L, Braziel, RM, Müller-Hermelink, HK, Campo, E, Gascoyne, RD, Staudt, LM, and Chan, WC. "Cyclin D1-negative mantle cell lymphoma: A clinicopathologic study based on gene expression profiling." Blood 106.13 (2005): 4315-4321.
PMID
16123218
Source
scival
Published In
Blood
Volume
106
Issue
13
Publish Date
2005
Start Page
4315
End Page
4321
DOI
10.1182/blood-2005-04-1753

Lymphoma-infiltrating immune cells [1] (multiple letters)

Authors
Kobayashi, K; Murashige, N; Jr, YK; Naresh, KN; Gajewski, TF; Dave, SS; Staudt, LM
MLA Citation
Kobayashi, K, Murashige, N, Jr, YK, Naresh, KN, Gajewski, TF, Dave, SS, and Staudt, LM. "Lymphoma-infiltrating immune cells [1] (multiple letters)." New England Journal of Medicine 352.7 (2005): 724-725.
PMID
15719444
Source
scival
Published In
The New England journal of medicine
Volume
352
Issue
7
Publish Date
2005
Start Page
724
End Page
725
DOI
10.1056/NEJM200502173520717

The biology of human lymphoid malignancies revealed by gene expression profiling

Gene expression profiling provides a quantitative molecular framework for the study of human lymphomas. This genomic technology has revealed that existing diagnostic categories are comprised of multiple molecularly and clinically distinct diseases. Diffuse large B-cell lymphoma (DLBCL), for example, consists of three gene expression subgroups, termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). These DLBCL subgroups arise from different stages of normal B-cell differentiation, utilize distinct oncogenic mechanisms, and differ in their ability to be cured by chemotherapy. Key regulatory factors and their target genes are differentially expressed among these subgroups, including BCL-6, Blimp-1, and XBP1. ABC DLBCL and PMBL depend upon constitutive activation of the NF-κB pathway for their survival but GCB DLBCL does not, demonstrating that this pathway is a potential therapeutic target for certain DLBCL subgroups. In DLBCL, mantle cell lymphoma, and follicular lymphoma, gene expression profiling has also been used to create gene expression-based models of survival, which have identified the biological characteristics of the tumors that influence their clinical behavior. In mantle cell lymphoma, the length of survival following diagnosis is primarily influenced by the tumor proliferation rate, which can be quantitatively measured by a proliferation gene expression "signature." Based on this accurate measure, the proliferation rate can now be viewed as an integration of several oncogenic lesions that each increase progression from the G1 to the S phase of the cell cycle. In DLBCL and follicular lymphoma, gene expression profiling has revealed that the molecular characteristics of non-malignant tumor-infiltrating immune cells have a major influence on the length of survival. The implications of these insights for the diagnosis and treatment of non-Hodgkin lymphomas are discussed. © 2005 Elsevier Inc. All rights reserved.

Authors
Staudt, LM; Dave, S
MLA Citation
Staudt, LM, and Dave, S. "The biology of human lymphoid malignancies revealed by gene expression profiling." Advances in Immunology 87 (2005): 163-208.
PMID
16102574
Source
scival
Published In
Advances in immunology
Volume
87
Publish Date
2005
Start Page
163
End Page
208
DOI
10.1016/S0065-2776(05)87005-1

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Authors
Dave, SS; Wright, G; Tan, B; Rosenwald, A; Gascoyne, RD; Chan, WC; Fisher, RI; Braziel, RM; Rimsza, LM; Grogan, TM; Miller, TP; LeBlanc, M; Greiner, TC; Weisenburger, DD; Lynch, JC; Vose, J; Armitage, JO; Smeland, EB; Kvaloy, S; Holte, H; Delabie, J; Connors, JM; Lansdorp, PM; Ouyang, Q; Lister, TA; Davies, AJ; Norton, AJ; Muller-Hermelink, HK; Ott, G; Campo, E; Montserrat, E; Wilson, WH; Jaffe, ES; Simon, R; Yang, L; Powell, J; Zhao, H; Goldschmidt, N; Chiorazzi, M; Staudt, LM
MLA Citation
Dave, SS, Wright, G, Tan, B, Rosenwald, A, Gascoyne, RD, Chan, WC, Fisher, RI, Braziel, RM, Rimsza, LM, Grogan, TM, Miller, TP, LeBlanc, M, Greiner, TC, Weisenburger, DD, Lynch, JC, Vose, J, Armitage, JO, Smeland, EB, Kvaloy, S, Holte, H, Delabie, J, Connors, JM, Lansdorp, PM, Ouyang, Q, Lister, TA, Davies, AJ, Norton, AJ, Muller-Hermelink, HK, Ott, G, Campo, E, Montserrat, E, Wilson, WH, Jaffe, ES, Simon, R, Yang, L, Powell, J, Zhao, H, Goldschmidt, N, Chiorazzi, M, and Staudt, LM. "Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells." N Engl J Med 351.21 (November 18, 2004): 2159-2169.
PMID
15548776
Source
pubmed
Published In
The New England journal of medicine
Volume
351
Issue
21
Publish Date
2004
Start Page
2159
End Page
2169
DOI
10.1056/NEJMoa041869

BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DL-BCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32; q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14; 18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.

Authors
Iqbal, J; Sanger, WG; Horsman, DE; Rosenwald, A; Pickering, DL; Dave, B; Dave, S; Xiao, L; Cao, K; Zhu, Q; Sherman, S; Hans, CP; Weisenburger, DD; Greiner, TC; Gascoyne, RD; Ott, G; Müller-Hermelink, HK; Delabie, J; Braziel, RM; Jaffe, ES; Campo, E; Lynch, JC; Connors, JM; Vose, JM; Armitage, JO; Grogan, TM; Staudt, LM; Chan, WC
MLA Citation
Iqbal, J, Sanger, WG, Horsman, DE, Rosenwald, A, Pickering, DL, Dave, B, Dave, S, Xiao, L, Cao, K, Zhu, Q, Sherman, S, Hans, CP, Weisenburger, DD, Greiner, TC, Gascoyne, RD, Ott, G, Müller-Hermelink, HK, Delabie, J, Braziel, RM, Jaffe, ES, Campo, E, Lynch, JC, Connors, JM, Vose, JM, Armitage, JO, Grogan, TM, Staudt, LM, and Chan, WC. "BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma." American Journal of Pathology 165.1 (2004): 159-166.
PMID
15215171
Source
scival
Published In
American Journal of Pathology
Volume
165
Issue
1
Publish Date
2004
Start Page
159
End Page
166

Cost-effectiveness considerations in the treatment of essential thrombocythemia.

Factors that influence the choice of anagrelide, hydroxyurea, or interferon-alfa (IFN-alpha) for treatment of essential thrombocythemia include efficacy, toxicity, and cost. Anagrelide has the US Food and Drug Administration's approval to be used for treating patients with thrombocythemia secondary to chronic myeloproliferative disorders. In contrast, the use of IFN-alpha and hydroxyurea are considered "off-label." We performed an incremental cost-effectiveness analysis to compare anagrelide, hydroxyurea, and IFN-alpha for treating essential thrombocythemia, in terms of estimated impact on life expectancy. The case used for this analysis was of a 40-year-old man with essential thrombocythemia. Clinical assumptions were based on information obtained from nonrandomized clinical trials, and the economic assumptions were derived from information abstracted from observational studies. Lifelong treatment use of anagrelide versus hydroxyurea would cost approximately $72,000 per additional year of life gained, while the use of IFN-alpha was found to be both more costly and less effective than anagrelide. The results were very sensitive to the risk of leukemia caused by hydroxyurea, with an incremental cost-effectiveness of anagrelide compared with hydroxyurea of $156,969 per additional year of life gained if the lifetime leukemia risk drops from a baseline of .08 to.05. Given that many commonly used medical interventions cost in the range of $50,000 to $100,000 per year of life gained, and the generally poor outcome associated with treatment-related leukemia that can result from hydroxyurea, anagrelide could be considered a therapeutic alternative that is clinically effective at an acceptable cost.

Authors
Golub, R; Adams, J; Dave, S; Bennett, CL
MLA Citation
Golub, R, Adams, J, Dave, S, and Bennett, CL. "Cost-effectiveness considerations in the treatment of essential thrombocythemia." Seminars in oncology 29.3 Suppl 10 (June 2002): 28-32.
PMID
12096355
Source
epmc
Published In
Seminars in Oncology
Volume
29
Issue
3 Suppl 10
Publish Date
2002
Start Page
28
End Page
32
DOI
10.1053/sonc.2002.33758

Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase.

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant neurodegenerative disorder affecting motor neurons and is associated with mutations in the Cu,Zn superoxide dismutase gene (SOD1) in a subset (approximately 15%) of FALS families. We analyzed 158 FALS patients from 27 families with mutations in SOD1. The mean age of onset was 45.5 +/- 8.9 years, and the mean duration of disease was 3.4 years. Forty-seven different mutations in SOD1 of FALS patients have been described worldwide. In North America, the ala4val mutation is the most common. In our patients, the ala4val mutation was associated with the most rapid progression of disease. The mean duration of disease was 1.0 +/- 0.4 years, which is significantly less than the mean duration of disease for FALS patients with mutations in SOD1 other than ala4val (p < 0.001). The duration of disease for the glu100gly mutation, 5.1 +/- 3.3 years, was significantly longer than the ala4val mutation (p < 0.001). We constructed Kaplan-Meier survival curves for the age of onset and duration of the disease for three groups of patients having mutations in SOD1: (1) ala4val; (2) glu100gly; and (3) ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly, i.e., the entire patient population. There was no correlation between the genotype and the age of onset; 50% of affected individuals developed symptoms of ALS by the age of 47 years. As more data are collected, a more accurate prognostication of a patient's survival may be possible for specific SOD1 mutations.

Authors
Juneja, T; Pericak-Vance, MA; Laing, NG; Dave, S; Siddique, T
MLA Citation
Juneja, T, Pericak-Vance, MA, Laing, NG, Dave, S, and Siddique, T. "Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase." Neurology 48.1 (January 1997): 55-57.
PMID
9008494
Source
pubmed
Published In
Neurology
Volume
48
Issue
1
Publish Date
1997
Start Page
55
End Page
57

ATP receptor activation potentiates a voltage-dependent Ca channel in hippocampal neurons

Activation of a purinergic P2 receptor by adenosine 5'-triphosphate (ATP) has previously been shown to open a non-selective cation channel with a reversal potential of approximately 0 mV. We examined the effects of P2 receptor activation on voltage-gated ionic currents in acutely isolated CA3 pyramidal neurons from guinea pig hippocampus using the whole-cell-patch technique. Under conditions designed to isolate current through voltage-dependent Ca channels (I(Ca)), ATP (50 μM) potentiated I(Ca) by 36%. This increase in I(Ca) desensitized back to control levels within 4 min. In contrast to the non-selective cation channel, I(Ca) elicited from a holding potential (HP) of -100 mV showed significant potentiation in response to ATP when depolarized to a test potential (TP) of -10 mV but showed no effect on I(Ca) when the same neuron was alternately depolarized to TP = -70 mV. No change in holding current at HP = -100 mV occurred. Tail currents were unaffected by ATP exposure suggesting that I(Ca) potentiation was not due to modulation of L-type Ca channels. This potentiation was also observed either with ATP-γ-s, the slowly hydrolyzable ATP analog, or with ATP in the presence of α, β-methylene-ADP, an ectonucleotidase inhibitor, indicating that the effects observed were not due to activation of an adenosine receptor that required ATP hydrolysis. The potentiation of I(Ca) was not observed with the P(2X) agonist, β,γ-methylene-ATP. These results suggest that ATP receptors can modulate voltage- as well as ligand-gated channels permeable to calcium and may play an important role in the dynamics of intracellular Ca2+ in these neurons.

Authors
Dave, S; Mogul, DJ
MLA Citation
Dave, S, and Mogul, DJ. "ATP receptor activation potentiates a voltage-dependent Ca channel in hippocampal neurons." Brain Research 715.1-2 (1996): 208-216.
PMID
8739640
Source
scival
Published In
Brain Research
Volume
715
Issue
1-2
Publish Date
1996
Start Page
208
End Page
216
DOI
10.1016/0006-8993(95)01588-4
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