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He, Yiping

Positions:

Assistant Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

Ph.D. — University of Pennsylvania

Post Doctoral Fellow, Pathology

Johns Hopkins University

Howard Hughes Researcher, Pathology

Johns Hopkins University

Research Associate, Pathology

Johns Hopkins University

Grants:

Exploiting MTAP for more effective treatment of glioblastoma with temozolomide

Administered By
Pathology
AwardedBy
Southeastern Brain Tumor Foundation
Role
Principal Investigator
Start Date
June 21, 2016
End Date
June 30, 2017

Developing novel mouse models for medulloblastoma

Administered By
Pathology
AwardedBy
Circle of Service Foundation
Role
Principal Investigator
Start Date
December 09, 2013
End Date
June 08, 2017

Automated Library Preparation System for Next-Generation Sequencing

Administered By
Biology
AwardedBy
North Carolina Biotechnology Center
Role
Major User
Start Date
September 15, 2014
End Date
September 14, 2015

Publications:

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. Additionally, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell of origin for glioma; thus, altering the progression of tumorigenesis. Additionally, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell of origin for gliomas.

Authors
Pirozzi, CJ; Carpenter, AB; Waitkus, MS; Wang, CY; Zhu, H; Hansen, LJ; Chen, LH; Greer, PK; Feng, J; Wang, Y; Bock, CB; Fan, P; Spasojevic, I; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Carpenter, AB, Waitkus, MS, Wang, CY, Zhu, H, Hansen, LJ, Chen, LH, Greer, PK, Feng, J, Wang, Y, Bock, CB, Fan, P, Spasojevic, I, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression." Molecular cancer research : MCR (February 2017).
PMID
28148827
Source
epmc
Published In
Molecular cancer research : MCR
Publish Date
2017
DOI
10.1158/1541-7786.mcr-16-0485

Alternative Splicing Provides a Novel Molecular Mechanism for Prostatic Small-cell Neuroendocrine Carcinoma.

Authors
Feng, N; Yin, Y; He, Y; Huang, J
MLA Citation
Feng, N, Yin, Y, He, Y, and Huang, J. "Alternative Splicing Provides a Novel Molecular Mechanism for Prostatic Small-cell Neuroendocrine Carcinoma." European urology 71.1 (January 2017): 79-80.
PMID
27481176
Source
epmc
Published In
European Urology
Volume
71
Issue
1
Publish Date
2017
Start Page
79
End Page
80
DOI
10.1016/j.eururo.2016.07.046

Molecular Signature to Risk-Stratify Prostate Cancer of Intermediate Risk.

A new 30-gene signature has been described that separates prostate cancers of Gleason score ≤6 from those of Gleason score ≥8. It provides independent prognostic information for prostate cancers of intermediate risk (Gleason score of 7), which has the potential to stratify these patients into different risk groups. Clin Cancer Res; 23(1); 6-8. ©2016 AACRSee related article by Sinnott et al., p. 81.

Authors
Yin, Y; Zhang, Q; Zhang, H; He, Y; Huang, J
MLA Citation
Yin, Y, Zhang, Q, Zhang, H, He, Y, and Huang, J. "Molecular Signature to Risk-Stratify Prostate Cancer of Intermediate Risk." Clinical cancer research : an official journal of the American Association for Cancer Research 23.1 (January 2017): 6-8.
Website
http://hdl.handle.net/10161/13092
PMID
27803045
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
1
Publish Date
2017
Start Page
6
End Page
8
DOI
10.1158/1078-0432.ccr-16-2400

Prevalence of deleterious ATM germline mutations in gastric cancer patients.

Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.

Authors
Huang, D-S; Tao, H-Q; He, X-J; Long, M; Yu, S; Xia, Y-J; Wei, Z; Xiong, Z; Jones, S; He, Y; Yan, H; Wang, X
MLA Citation
Huang, D-S, Tao, H-Q, He, X-J, Long, M, Yu, S, Xia, Y-J, Wei, Z, Xiong, Z, Jones, S, He, Y, Yan, H, and Wang, X. "Prevalence of deleterious ATM germline mutations in gastric cancer patients." Oncotarget 6.38 (December 2015): 40953-40958.
PMID
26506520
Source
epmc
Published In
Oncotarget
Volume
6
Issue
38
Publish Date
2015
Start Page
40953
End Page
40958
DOI
10.18632/oncotarget.5944

MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation." October 1, 2014.
Source
wos-lite
Published In
Cancer Research
Volume
74
Issue
19
Publish Date
2014
DOI
10.1158/1538-7445.AM2014-LB-82

Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma

Authors
Pirozzi, CJ; Wang, CY; Carpenter, AB; Zhu, H; Greer, PK; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Wang, CY, Carpenter, AB, Zhu, H, Greer, PK, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
63
End Page
63
DOI
10.1158/1538-7445.AM2014-63

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature genetics 46.7 (July 2014): 726-730.
PMID
24880341
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature Genetics 46.7 (June 1, 2014): 726-730.
Source
crossref
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.

Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, PJ, Pirozzi, CJ, Healy, P, Reitman, ZJ, Lipp, E, Rasheed, BA, Yang, R, Diplas, BH, Wang, Z, Greer, PK, Zhu, H, Wang, CY, Carpenter, AB, Friedman, H, Friedman, AH, Keir, ST, He, J, He, Y, McLendon, RE, Herndon, JE, Yan, H, and Bigner, DD. "Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas." Oncotarget 5.6 (March 2014): 1515-1525.
PMID
24722048
Source
epmc
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1515
End Page
1525

The genetic landscape of anaplastic astrocytoma.

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Authors
Killela, PJ; Pirozzi, CJ; Reitman, ZJ; Jones, S; Rasheed, BA; Lipp, E; Friedman, H; Friedman, AH; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Killela, PJ, Pirozzi, CJ, Reitman, ZJ, Jones, S, Rasheed, BA, Lipp, E, Friedman, H, Friedman, AH, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "The genetic landscape of anaplastic astrocytoma." Oncotarget 5.6 (March 2014): 1452-1457.
PMID
24140581
Source
epmc
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1452
End Page
1457

Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.

Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.

Authors
Wortham, M; Guo, C; Zhang, M; Song, L; Lee, B-K; Iyer, VR; Furey, TS; Crawford, GE; Yan, H; He, Y
MLA Citation
Wortham, M, Guo, C, Zhang, M, Song, L, Lee, B-K, Iyer, VR, Furey, TS, Crawford, GE, Yan, H, and He, Y. "Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma." PloS one 9.9 (January 2014): e107156-.
Website
http://hdl.handle.net/10161/10681
PMID
25198066
Source
epmc
Published In
PloS one
Volume
9
Issue
9
Publish Date
2014
Start Page
e107156
DOI
10.1371/journal.pone.0107156

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.

KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation." Oncotarget 4.11 (November 2013): 2144-2153.
PMID
24240169
Source
pubmed
Published In
Oncotarget
Volume
4
Issue
11
Publish Date
2013
Start Page
2144
End Page
2153
DOI
10.18632/oncotarget.1555

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Authors
Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, T-C; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I-M; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, T-L; Wentzensen, N; Wood, LD; Zhang, M; McLendon, RE; Bigner, DD; Kinzler, KW; Vogelstein, B; Papadopoulos, N; Yan, H
MLA Citation
Killela, PJ, Reitman, ZJ, Jiao, Y, Bettegowda, C, Agrawal, N, Diaz, LA, Friedman, AH, Friedman, H, Gallia, GL, Giovanella, BC, Grollman, AP, He, T-C, He, Y, Hruban, RH, Jallo, GI, Mandahl, N, Meeker, AK, Mertens, F, Netto, GJ, Rasheed, BA, Riggins, GJ, Rosenquist, TA, Schiffman, M, Shih, I-M, Theodorescu, D, Torbenson, MS, Velculescu, VE, Wang, T-L, Wentzensen, N, Wood, LD, Zhang, M, McLendon, RE, Bigner, DD, Kinzler, KW, Vogelstein, B, Papadopoulos, N, and Yan, H. "TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal." Proc Natl Acad Sci U S A 110.15 (April 9, 2013): 6021-6026.
PMID
23530248
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
15
Publish Date
2013
Start Page
6021
End Page
6026
DOI
10.1073/pnas.1303607110

ABERRANT Otx2 EXPRESSION ENHANCES MIGRATION AND INDUCES ECTOPIC PROLIFERATION OF HINDBRAIN NEURONAL PROGENITOR CELLS

Authors
Wortham, M; Reitman, Z; He, Y; Bigner, D; Yan, H
MLA Citation
Wortham, M, Reitman, Z, He, Y, Bigner, D, and Yan, H. "ABERRANT Otx2 EXPRESSION ENHANCES MIGRATION AND INDUCES ECTOPIC PROLIFERATION OF HINDBRAIN NEURONAL PROGENITOR CELLS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
2
End Page
2

GLOBAL IDENTIFICATION OF MLL2-TARGETED LOCI REVEALS MLL2'S ROLE IN DIVERSE SIGNALING PATHWAYS

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, L; Kernagis, D; Qin, X; Cho, Y-W; Chi, J-T; Grant, G; McLendon, R; Yan, H; Ge, K; Papadopoulos, N; Bigner, D; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, L, Kernagis, D, Qin, X, Cho, Y-W, Chi, J-T, Grant, G, McLendon, R, Yan, H, Ge, K, Papadopoulos, N, Bigner, D, and He, Y. "GLOBAL IDENTIFICATION OF MLL2-TARGETED LOCI REVEALS MLL2'S ROLE IN DIVERSE SIGNALING PATHWAYS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
9
End Page
9

Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.

Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.

Authors
Jin, G; Reitman, ZJ; Duncan, CG; Spasojevic, I; Gooden, DM; Rasheed, BA; Yang, R; Lopez, GY; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Jin, G, Reitman, ZJ, Duncan, CG, Spasojevic, I, Gooden, DM, Rasheed, BA, Yang, R, Lopez, GY, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas." Cancer Res 73.2 (January 15, 2013): 496-501.
PMID
23204232
Source
pubmed
Published In
Cancer Research
Volume
73
Issue
2
Publish Date
2013
Start Page
496
End Page
501
DOI
10.1158/0008-5472.CAN-12-2852

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, LH; Kernagis, DN; Qin, X; Cho, Y-W; Chi, J-T; Grant, GA; McLendon, RE; Yan, H; Ge, K; Papadopoulos, N; Bigner, DD; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, LH, Kernagis, DN, Qin, X, Cho, Y-W, Chi, J-T, Grant, GA, McLendon, RE, Yan, H, Ge, K, Papadopoulos, N, Bigner, DD, and He, Y. "Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways." Proc Natl Acad Sci U S A 109.43 (October 23, 2012): 17603-17608.
PMID
23045699
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
43
Publish Date
2012
Start Page
17603
End Page
17608
DOI
10.1073/pnas.1208807109

Mutant IDH1 is required for IDH1 mutated tumor cell growth.

Frequent somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in gliomas, acute myeloid leukemias, chondrosarcomas, and other cancers, providing a likely avenue for targeted cancer therapy. However, whether mutant IDH1 protein is required for maintaining IDH1 mutated tumor cell growth remains unknown. Here, using a genetically engineered inducible system, we report that selective suppression of endogenous mutant IDH1 expression in HT1080, a fibrosarcoma cell line with a native IDH1(R132C) heterozygous mutation, significantly inhibits cell proliferation and decreases clonogenic potential. Our findings offer insights into changes that may contribute to the inhibition of cell proliferation and offer a strong preclinical rationale for utilizing mutant IDH1 as a valid therapeutic target.

Authors
Jin, G; Pirozzi, CJ; Chen, LH; Lopez, GY; Duncan, CG; Feng, J; Spasojevic, I; Bigner, DD; He, Y; Yan, H
MLA Citation
Jin, G, Pirozzi, CJ, Chen, LH, Lopez, GY, Duncan, CG, Feng, J, Spasojevic, I, Bigner, DD, He, Y, and Yan, H. "Mutant IDH1 is required for IDH1 mutated tumor cell growth." Oncotarget 3.8 (August 2012): 774-782.
PMID
22885298
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
8
Publish Date
2012
Start Page
774
End Page
782
DOI
10.18632/oncotarget.577

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Authors
Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H
MLA Citation
Jiao, Y, Killela, PJ, Reitman, ZJ, Rasheed, AB, Heaphy, CM, de Wilde, RF, Rodriguez, FJ, Rosemberg, S, Oba-Shinjo, SM, Nagahashi Marie, SK, Bettegowda, C, Agrawal, N, Lipp, E, Pirozzi, C, Lopez, G, He, Y, Friedman, H, Friedman, AH, Riggins, GJ, Holdhoff, M, Burger, P, McLendon, R, Bigner, DD, Vogelstein, B, Meeker, AK, Kinzler, KW, Papadopoulos, N, Diaz, LA, and Yan, H. "Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas." Oncotarget 3.7 (July 2012): 709-722.
PMID
22869205
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
7
Publish Date
2012
Start Page
709
End Page
722
DOI
10.18632/oncotarget.588

Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells.

Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation.

Authors
Wortham, M; Jin, G; Sun, JL; Bigner, DD; He, Y; Yan, H
MLA Citation
Wortham, M, Jin, G, Sun, JL, Bigner, DD, He, Y, and Yan, H. "Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells." PLoS One 7.4 (2012): e36211-.
PMID
22558385
Source
pubmed
Published In
PloS one
Volume
7
Issue
4
Publish Date
2012
Start Page
e36211
DOI
10.1371/journal.pone.0036211

Altered telomeres in tumors with ATRX and DAXX mutations.

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

Authors
Heaphy, CM; de Wilde, RF; Jiao, Y; Klein, AP; Edil, BH; Shi, C; Bettegowda, C; Rodriguez, FJ; Eberhart, CG; Hebbar, S; Offerhaus, GJ; McLendon, R; Rasheed, BA; He, Y; Yan, H; Bigner, DD; Oba-Shinjo, SM; Marie, SKN; Riggins, GJ; Kinzler, KW; Vogelstein, B; Hruban, RH; Maitra, A; Papadopoulos, N; Meeker, AK
MLA Citation
Heaphy, CM, de Wilde, RF, Jiao, Y, Klein, AP, Edil, BH, Shi, C, Bettegowda, C, Rodriguez, FJ, Eberhart, CG, Hebbar, S, Offerhaus, GJ, McLendon, R, Rasheed, BA, He, Y, Yan, H, Bigner, DD, Oba-Shinjo, SM, Marie, SKN, Riggins, GJ, Kinzler, KW, Vogelstein, B, Hruban, RH, Maitra, A, Papadopoulos, N, and Meeker, AK. "Altered telomeres in tumors with ATRX and DAXX mutations." Science 333.6041 (July 22, 2011): 425-.
PMID
21719641
Source
pubmed
Published In
Science
Volume
333
Issue
6041
Publish Date
2011
Start Page
425
DOI
10.1126/science.1207313

METABOLOMIC PROFILING OF A GLIOMA CELL LINE EXPRESSING IDH1 AND IDH2 MUTANTS

Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, ZJ, Jin, G, Karoly, ED, Spasojevic, I, Yang, J, Kinzler, KW, He, Y, Bigner, DD, Vogelstein, B, and Yan, H. "METABOLOMIC PROFILING OF A GLIOMA CELL LINE EXPRESSING IDH1 AND IDH2 MUTANTS." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I22
End Page
I23

CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS

Authors
He, Y; Lopez, G; Grant, G; Fuchs, H; Leithe, L; Gururangan, S; Bigner, D; Yan, H; Mclendon, R
MLA Citation
He, Y, Lopez, G, Grant, G, Fuchs, H, Leithe, L, Gururangan, S, Bigner, D, Yan, H, and Mclendon, R. "CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS." May 2011.
PMID
23659599
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I30
End Page
I30

Profiling the effects of IDH1 and IDH2 mutants on the glioma cell metabolome

Authors
Yan, H; Reitman, ZJ; Jin, G; Spasojevic, I; He, Y; Bigner, DD; Karoly, ED; Yang, J; Kinzler, KW; Vogelstein, B
MLA Citation
Yan, H, Reitman, ZJ, Jin, G, Spasojevic, I, He, Y, Bigner, DD, Karoly, ED, Yang, J, Kinzler, KW, and Vogelstein, B. "Profiling the effects of IDH1 and IDH2 mutants on the glioma cell metabolome." April 15, 2011.
Source
wos-lite
Published In
Cancer Research
Volume
71
Publish Date
2011
DOI
10.1158/1538-7445.AM2011-LB-257

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.

Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, ZJ, Jin, G, Karoly, ED, Spasojevic, I, Yang, J, Kinzler, KW, He, Y, Bigner, DD, Vogelstein, B, and Yan, H. "Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome." Proc Natl Acad Sci U S A 108.8 (February 22, 2011): 3270-3275.
PMID
21289278
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
8
Publish Date
2011
Start Page
3270
End Page
3275
DOI
10.1073/pnas.1019393108

The genetic landscape of the childhood cancer medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Authors
Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC-H; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SKN; Shinjo, SMO; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G et al.
MLA Citation
Parsons, DW, Li, M, Zhang, X, Jones, S, Leary, RJ, Lin, JC-H, Boca, SM, Carter, H, Samayoa, J, Bettegowda, C, Gallia, GL, Jallo, GI, Binder, ZA, Nikolsky, Y, Hartigan, J, Smith, DR, Gerhard, DS, Fults, DW, VandenBerg, S, Berger, MS, Marie, SKN, Shinjo, SMO, Clara, C, Phillips, PC, Minturn, JE, Biegel, JA, Judkins, AR, Resnick, AC, Storm, PB, Curran, T, He, Y, Rasheed, BA, Friedman, HS, Keir, ST, McLendon, R, Northcott, PA, Taylor, MD, Burger, PC, Riggins, GJ, Karchin, R, and Parmigiani, G et al. "The genetic landscape of the childhood cancer medulloblastoma." Science 331.6016 (January 28, 2011): 435-439.
PMID
21163964
Source
pubmed
Published In
Science
Volume
331
Issue
6016
Publish Date
2011
Start Page
435
End Page
439
DOI
10.1126/science.1198056

Heteroplasmic mitochondrial DNA mutations in normal and tumour cells

The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype. © 2010 Macmillan Publishers Limited. All rights reserved.

Authors
He, Y; Wu, J; Dressman, DC; Iacobuzio-Donahue, C; Markowitz, SD; Velculescu, VE; Jr, LAD; Kinzler, KW; Vogelstein, B; Papadopoulos, N
MLA Citation
He, Y, Wu, J, Dressman, DC, Iacobuzio-Donahue, C, Markowitz, SD, Velculescu, VE, Jr, LAD, Kinzler, KW, Vogelstein, B, and Papadopoulos, N. "Heteroplasmic mitochondrial DNA mutations in normal and tumour cells." Nature 464.7288 (2010): 610-614.
PMID
20200521
Source
scival
Published In
Nature
Volume
464
Issue
7288
Publish Date
2010
Start Page
610
End Page
614
DOI
10.1038/nature08802

Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A.

Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo beta-selection, during which cells expressing functionally rearranged TCRbeta proliferate and differentiate into CD4(+)CD8(+) progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulate Notch1 transcription in pre-beta-selected thymocytes. Following successful beta-selection, pre-TCR signaling rapidly inhibits Notch1 transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 in Notch1 down-regulation, post-beta-selected Id3-deficient thymocytes maintain Notch1 transcription, whereas enforced Id3 expression decreases Notch1 expression and abrogates Notch1-dependent T-cell survival. These data provide new insights into Notch1 regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling and Notch1 expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.

Authors
Yashiro-Ohtani, Y; He, Y; Ohtani, T; Jones, ME; Shestova, O; Xu, L; Fang, TC; Chiang, MY; Intlekofer, AM; Blacklow, SC; Zhuang, Y; Pear, WS
MLA Citation
Yashiro-Ohtani, Y, He, Y, Ohtani, T, Jones, ME, Shestova, O, Xu, L, Fang, TC, Chiang, MY, Intlekofer, AM, Blacklow, SC, Zhuang, Y, and Pear, WS. "Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A." Genes Dev 23.14 (July 15, 2009): 1665-1676.
PMID
19605688
Source
pubmed
Published In
Genes & development
Volume
23
Issue
14
Publish Date
2009
Start Page
1665
End Page
1676
DOI
10.1101/gad.1793709

Sensitive digital quantification of DNA methylation in clinical samples

Analysis of abnormally methylated genes is increasingly important in basic research and in the development of cancer biomarkers. We have developed methyl-BEAMing technology to enable absolute quantification of the number of methylated molecules in a sample. Individual DNA fragments are amplified and analyzed either by flow cytometry or next-generation sequencing. We demonstrate enumeration of as few as one methylated molecule in 5,000 unmethylated molecules in DNA from plasma or fecal samples. Using methylated vimentin as a biomarker in plasma samples, methyl-BEAMing detected 59% of cancer cases. In early-stage colorectal cancers, this sensitivity was four times more than that obtained by assaying serum-carcinoembryonic antigen (CEA). With stool samples, methyl-BEAMing detected 41% of cancers and 45% of advanced adenomas. In addition to diagnostic and prognostic applications, this digital quantification of rare methylation events should be applicable to preclinical assessment of new epigenetic biomarkers and quantitative analyses in epigenetic research. © 2009 Nature America, Inc. All rights reserved.

Authors
Li, M; Chen, W-D; Papadopoulos, N; Goodman, SN; Bjerregaard, NC; Laurberg, S; Levin, B; Juhl, H; Arber, N; Moinova, H; Durkee, K; Schmidt, K; He, Y; Diehl, F; Velculescu, VE; Zhou, S; Diaz, LA; Kinzler, KW; Markowitz, SD; Vogelstein, B
MLA Citation
Li, M, Chen, W-D, Papadopoulos, N, Goodman, SN, Bjerregaard, NC, Laurberg, S, Levin, B, Juhl, H, Arber, N, Moinova, H, Durkee, K, Schmidt, K, He, Y, Diehl, F, Velculescu, VE, Zhou, S, Diaz, LA, Kinzler, KW, Markowitz, SD, and Vogelstein, B. "Sensitive digital quantification of DNA methylation in clinical samples." Nature Biotechnology 27.9 (2009): 858-863.
PMID
19684580
Source
scival
Published In
Nature Biotechnology
Volume
27
Issue
9
Publish Date
2009
Start Page
858
End Page
863
DOI
10.1038/nbt.1559

The antisense transcriptomes of human cells

Transcription in mammalian cells can be assessed at a genome-wide level, but it has been difficult to reliably determine whether individual transcripts are derived from the plus or minus strands of chromosomes. This distinction can be critical for understanding the relationship between known transcripts (sense) and the complementary antisense transcripts that may regulate them. Here, we describe a technique that can be used to (i) identify the DNA strand of origin for any particular RNA transcript, and (ii) quantify the number of sense and antisense transcripts from expressed genes at a global level. We examined five different human cell types and in each case found evidence for antisense transcripts in 2900 to 6400 human genes. The distribution of antisense transcripts was distinct from that of sense transcripts, was nonrandom across the genome, and differed among cell types. Antisense transcripts thus appear to be a pervasive feature of human cells, which suggests that they are a fundamental component of gene regulation.

Authors
He, Y; Vogelstein, B; Velculescu, VE; Papadopoulos, N; Kinzler, KW
MLA Citation
He, Y, Vogelstein, B, Velculescu, VE, Papadopoulos, N, and Kinzler, KW. "The antisense transcriptomes of human cells." Science 322.5909 (2008): 1855-1857.
PMID
19056939
Source
scival
Published In
Science
Volume
322
Issue
5909
Publish Date
2008
Start Page
1855
End Page
1857
DOI
10.1126/science.1163853

Constitutive Notch signalling promotes CD4 CD8 thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals.

Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the alphabeta T-cell lineage and plays an important role in regulating beta-selection in CD4(-)CD8(-) double-negative (DN) thymocytes. However, the role played by Notch in promoting the development of CD4(+)CD8(+) double-positive (DP) thymocytes is poorly characterized. Here, we demonstrate that the introduction of a constitutively active Notch1 (ICN1) construct into RAG(-/-) lymphocyte precursors resulted in the generation of DP thymocytes in in vitro T-cell culture systems. Notably, developmental rescue was dependent not only on the presence of an intact Notch1 RAM domain but also on Delta-like signals, as ICN1-induced DP development in RAG(-/-) thymocytes occurred within an intact thymus or in OP9-DL1 co-cultures, but not in OP9-control co-cultures. Interestingly, ICN1 expression in SLP-76(-/-) precursors resulted in only a minimal developmental rescue to the immature CD8(+) single-positive stage, suggesting that Notch is utilizing the same signalling pathway as the pre-TCR complex. In support of this, ICN1 introduction resulted in the activation of the ERK-MAPK-signalling cascade in RAG(-/-) thymocytes. Taken together, these studies demonstrate that constitutive Notch signalling can bypass beta-selection during early T-cell development by inducing pre-TCR-like signals within a T-cell-promoting environment.

Authors
Michie, AM; Chan, AC; Ciofani, M; Carleton, M; Lefebvre, JM; He, Y; Allman, DM; Wiest, DL; Zúñiga-Pflücker, JC; Izon, DJ
MLA Citation
Michie, AM, Chan, AC, Ciofani, M, Carleton, M, Lefebvre, JM, He, Y, Allman, DM, Wiest, DL, Zúñiga-Pflücker, JC, and Izon, DJ. "Constitutive Notch signalling promotes CD4 CD8 thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals." International immunology 19.12 (December 2007): 1421-1430.
PMID
17981791
Source
epmc
Published In
International Immunology
Volume
19
Issue
12
Publish Date
2007
Start Page
1421
End Page
1430
DOI
10.1093/intimm/dxm113

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.

Authors
Wouters, BJ; Jordà, MA; Keeshan, K; Louwers, I; Erpelinck-Verschueren, CAJ; Tielemans, D; Langerak, AW; He, Y; Yashiro-Ohtani, Y; Zhang, P; Hetherington, CJ; Verhaak, RGW; Valk, PJM; Löwenberg, B; Tenen, DG; Pear, WS; Delwel, R
MLA Citation
Wouters, BJ, Jordà, MA, Keeshan, K, Louwers, I, Erpelinck-Verschueren, CAJ, Tielemans, D, Langerak, AW, He, Y, Yashiro-Ohtani, Y, Zhang, P, Hetherington, CJ, Verhaak, RGW, Valk, PJM, Löwenberg, B, Tenen, DG, Pear, WS, and Delwel, R. "Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1." Blood 110.10 (November 2007): 3706-3714.
PMID
17671232
Source
epmc
Published In
Blood
Volume
110
Issue
10
Publish Date
2007
Start Page
3706
End Page
3714
DOI
10.1182/blood-2007-02-073486

Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia.

Tribbles homolog 2 (Trib2) was identified as a downregulated transcript in leukemic cells undergoing growth arrest. To investigate the effects of Trib2 in hematopoietic progenitors, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. Trib2-transduced bone marrow cells exhibited a growth advantage ex vivo and readily established factor-dependent cell lines. In vivo, Trib2-reconstituted mice uniformly developed fatal transplantable acute myelogenous leukemia (AML). In mechanistic studies, we found that Trib2 associated with and inhibited C/EBPalpha. Furthermore, Trib2 expression was elevated in a subset of human AML patient samples. Together, our data identify Trib2 as an oncogene that induces AML through a mechanism involving inactivation of C/EBPalpha.

Authors
Keeshan, K; He, Y; Wouters, BJ; Shestova, O; Xu, L; Sai, H; Rodriguez, CG; Maillard, I; Tobias, JW; Valk, P; Carroll, M; Aster, JC; Delwel, R; Pear, WS
MLA Citation
Keeshan, K, He, Y, Wouters, BJ, Shestova, O, Xu, L, Sai, H, Rodriguez, CG, Maillard, I, Tobias, JW, Valk, P, Carroll, M, Aster, JC, Delwel, R, and Pear, WS. "Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia." Cancer cell 10.5 (November 2006): 401-411.
PMID
17097562
Source
epmc
Published In
Cancer Cell
Volume
10
Issue
5
Publish Date
2006
Start Page
401
End Page
411
DOI
10.1016/j.ccr.2006.09.012

The colorectal microRNAome

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. These studies suggest that the human genome contains many more miRNAs than currently identified and provide an approach for the large-scale experimental cloning of novel human miRNAs in human tissues. © 2006 by The National Academy of Sciences of the USA.

Authors
Cummins, JM; He, Y; Leary, RJ; Pagliarini, R; Jr, LAD; Sjoblom, T; Barad, O; Bentwich, Z; Szafranska, AE; Labourier, E; Raymond, CK; Roberts, BS; Juhl, H; Kinzler, KW; Vogelstein, B; Velculescu, VE
MLA Citation
Cummins, JM, He, Y, Leary, RJ, Pagliarini, R, Jr, LAD, Sjoblom, T, Barad, O, Bentwich, Z, Szafranska, AE, Labourier, E, Raymond, CK, Roberts, BS, Juhl, H, Kinzler, KW, Vogelstein, B, and Velculescu, VE. "The colorectal microRNAome." Proceedings of the National Academy of Sciences of the United States of America 103.10 (2006): 3687-3692.
PMID
16505370
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
10
Publish Date
2006
Start Page
3687
End Page
3692
DOI
10.1073/pnas.0511155103

BEAMing: Single-molecule PCR on microparticles in water-in-oil emulsions

The most important biotechnological advances made in the 20th century involved methods that converted single DNA molecules into populations of identical DNA molecules. The first wave of techniques used cells (cloning) and the second used PCR. Cloning was advantageous because the populations arising from individual molecules were inherently separated. In contrast, each template required individual compartments (tubes) for PCR-based methods if separate products were desired. Emulsion PCR overcame this disadvantage by miniaturizing the compartments so that millions of templates could be individually amplified within a single tube3. BEAMing (beads, emulsions, amplification and magnetics) is a process built on emulsion PCR that (i) includes beads within the compartments and (ii) ensures that one strand of the PCR product is bound to the beads. After amplification, each compartment contains a bead that is coated with thousands of copies of the single DNA molecule originally present. These beads can be recovered with a magnet or by centrifugation. Beads obtained via BEAMing accurately reflect the DNA diversity present in template populations and this method can be used to determine what fraction of a DNA population contains a specific mutation. Because each bead contains thousands of molecules of the identical sequence, the signal to noise ratio obtained by hybridization or enzymatic assays is extremely high. Millions of beads can be analyzed within minutes using flow cytometry or optical scanning instruments. The DNA bound to beads also provides excellent templates for high-throughput sequencing. In this protocol we describe detailed methods for BEAMing, including a new technique for simultaneously generating 192 emulsions suitable for BEAMing. © 2006 Nature Publishing Group.

Authors
Diehl, F; Li, M; He, Y; Kinzler, KW; Vogelstein, B; Dressman, D
MLA Citation
Diehl, F, Li, M, He, Y, Kinzler, KW, Vogelstein, B, and Dressman, D. "BEAMing: Single-molecule PCR on microparticles in water-in-oil emulsions." Nature Methods 3.7 (2006): 551-559.
PMID
16791214
Source
scival
Published In
Nature Methods
Volume
3
Issue
7
Publish Date
2006
Start Page
551
End Page
559
DOI
10.1038/nmeth898

Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies.

Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.

Authors
Zweidler-McKay, PA; He, Y; Xu, L; Rodriguez, CG; Karnell, FG; Carpenter, AC; Aster, JC; Allman, D; Pear, WS
MLA Citation
Zweidler-McKay, PA, He, Y, Xu, L, Rodriguez, CG, Karnell, FG, Carpenter, AC, Aster, JC, Allman, D, and Pear, WS. "Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies." Blood 106.12 (December 2005): 3898-3906.
PMID
16118316
Source
epmc
Published In
Blood
Volume
106
Issue
12
Publish Date
2005
Start Page
3898
End Page
3906
DOI
10.1182/blood-2005-01-0355

Detection and quantification of mutations in the plasma of patients with colorectal tumors

The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon. © 2005 by The National Academy of Sciences of the USA.

Authors
Diehl, F; Li, M; Dressman, D; He, Y; Shen, D; Szabo, S; Jr, LAD; Goodman, SN; David, KA; Juhl, H; Kinzler, KW; Vogelstein, B
MLA Citation
Diehl, F, Li, M, Dressman, D, He, Y, Shen, D, Szabo, S, Jr, LAD, Goodman, SN, David, KA, Juhl, H, Kinzler, KW, and Vogelstein, B. "Detection and quantification of mutations in the plasma of patients with colorectal tumors." Proceedings of the National Academy of Sciences of the United States of America 102.45 (2005): 16368-16373.
PMID
16258065
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
45
Publish Date
2005
Start Page
16368
End Page
16373
DOI
10.1073/pnas.0507904102

Notch 1 signaling regulates peripheral T cell activation.

Notch signaling has been identified as an important regulator of leukocyte differentiation and thymic maturation. Less is known about the role of Notch signaling in regulating mature T cells. We examined the role of Notch 1 in regulating peripheral T cell activity in vitro and in vivo. Coligation of Notch 1 together with TCR and CD28 resulted in a dramatic inhibition of T cell activation, proliferation, and cytokine production. This effect was dependent on presenilin activity and induced the expression of HES-1, suggestive of Notch 1 signaling. Biochemical analysis demonstrated an inhibition of AKT and GSK3beta phosphorylation following Notch 1 engagement while other biochemical signals such as TCR and ERK phosphorylation remained intact. Similar effects were observed in vivo in an adoptive transfer model. Therefore, Notch 1 signaling may play an important role in regulating naive T cell activation and homeostasis.

Authors
Eagar, TN; Tang, Q; Wolfe, M; He, Y; Pear, WS; Bluestone, JA
MLA Citation
Eagar, TN, Tang, Q, Wolfe, M, He, Y, Pear, WS, and Bluestone, JA. "Notch 1 signaling regulates peripheral T cell activation." Immunity 20.4 (April 2004): 407-415.
PMID
15084270
Source
epmc
Published In
Immunity
Volume
20
Issue
4
Publish Date
2004
Start Page
407
End Page
415
DOI
10.1016/s1074-7613(04)00081-0

From the yolk sac to the spleen: New roles for Notch in regulating hematopoiesis.

Although Notch receptors are widely expressed during hematopoiesis, their roles outside of the T cell lineage are not well characterized. Two reports in this issue of Immunity show that Notch1 and Notch2, respectively, are required to generate the earliest embryonic hematopoietic stem cells and splenic marginal zone B cells. Thus, different Notch receptors have specific and nonoverlapping functions that influence multiple hematopoietic lineages at various stages of development.

Authors
Maillard, I; He, Y; Pear, WS
MLA Citation
Maillard, I, He, Y, and Pear, WS. "From the yolk sac to the spleen: New roles for Notch in regulating hematopoiesis." Immunity 18.5 (May 2003): 587-589.
PMID
12753735
Source
epmc
Published In
Immunity
Volume
18
Issue
5
Publish Date
2003
Start Page
587
End Page
589
DOI
10.1016/s1074-7613(03)00119-5

Notch signalling in B cells.

Notch signalling is likely to regulate multiple aspects of lymphoid development and function. During T cell development, Notch signalling is required for commitment of the earliest progenitor, and may also function during other developmental stages. T cell commitment from a common lymphoid progenitor occurs at the expense of B cell development, suggesting that Notch signalling inhibits the earliest stage of B lymphopoiesis. In contrast, recent evidence suggests that Notch promotes the development of marginal zone lymphocytes. Not only is Notch required for later stages of B cell development, but several viral proteins appear to utilize Notch signalling in B cells to mediate their functions. In this review, we will focus on potential roles of Notch signalling in B lymphopoiesis and also consider how viral proteins may utilize Notch signalling in B cells.

Authors
He, Y; Pear, WS
MLA Citation
He, Y, and Pear, WS. "Notch signalling in B cells." Seminars in cell & developmental biology 14.2 (April 2003): 135-142. (Review)
PMID
12651097
Source
epmc
Published In
Seminars in Cell and Developmental Biology
Volume
14
Issue
2
Publish Date
2003
Start Page
135
End Page
142
DOI
10.1016/s1084-9521(02)00182-9

The biology of chronic myelogenous leukemia:mouse models and cell adhesion.

Chronic myelogenous leukemia (CML) is a biphasic neoplasm of the bone marrow that is precipitated by the Philadelphia chromosome, a t(9;22) balanced translocation that encodes a constitutively activated nonreceptor tyrosine kinase termed P210(BCR-ABL). This oncoprotein has several intracellular functions; however, the most important effect of P210(BCR-ABL) leading to cell transformation is phosphorylation of signaling molecules through a constitutively active tyrosine kinase domain. Despite extensive knowledge of the structure and functional domains of BCR-ABL, its precise function in transformation is not known. Progress has been hampered, in part, by the lack of relevant CML models, as cell culture and in vitro assays do not mimic the pathogenesis of CML. Recently, there has been significant progress toward improving murine models that closely resemble human CML. This has allowed researchers to evaluate critical functions of BCR-ABL and has provided a model to test the efficacy of therapeutic medications that block these pathways. Our laboratory has developed two intersecting research programs to better understand the functioning of P210(BCR-ABL) in leukemogenesis. In one approach, we have developed a murine CML model by transferring HSCs that express BCR-ABL from a retroviral vector. All recipients develop a rapidly fatal MPD that shares several important features with CML. This model has been extremely useful for studying the function of BCR-ABL in the pathogenesis of CML. A second approach utilizes a quantitative cell detachment apparatus capable of measuring small changes in cell adhesion to investigate the mechanism by which P210(BCR-ABL) causes abnormal cell binding. Altered cell adhesion may contribute to the imbalance between proliferation and self-renewal in the hematopoietic progenitor compartment. To better understand the role abnormal adhesion may play in the development of leukemia, we have attempted to correlate the effects of functional P210(BCR-ABL) mutants in regulating adhesion and oncogenicity.

Authors
Wertheim, JA; Miller, JP; Xu, L; He, Y; Pear, WS
MLA Citation
Wertheim, JA, Miller, JP, Xu, L, He, Y, and Pear, WS. "The biology of chronic myelogenous leukemia:mouse models and cell adhesion." Oncogene 21.56 (December 2002): 8612-8628. (Review)
PMID
12476308
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
21
Issue
56
Publish Date
2002
Start Page
8612
End Page
8628
DOI
10.1038/sj.onc.1206089

The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.

The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Delta(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Delta(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML.

Authors
He, Y; Wertheim, JA; Xu, L; Miller, JP; Karnell, FG; Choi, JK; Ren, R; Pear, WS
MLA Citation
He, Y, Wertheim, JA, Xu, L, Miller, JP, Karnell, FG, Choi, JK, Ren, R, and Pear, WS. "The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl." Blood 99.8 (April 2002): 2957-2968.
PMID
11929787
Source
epmc
Published In
Blood
Volume
99
Issue
8
Publish Date
2002
Start Page
2957
End Page
2968
DOI
10.1182/blood.v99.8.2957

Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.

Notch1 signaling drives T cell development at the expense of B cell development from a common precursor, an effect that is dependent on a C-terminal Notch1 transcriptional activation domain. The function of Deltex1, initially identified as a positive modulator of Notch function in a genetic screen in Drosophila, is poorly understood. We now demonstrate that, in contrast to Notch1, enforced expression of Deltex1 in hematopoietic progenitors results in B cell development at the expense of T cell development in fetal thymic organ culture and in vivo. Consistent with these effects, Deltex1 antagonizes Notch1 signaling in transcriptional reporter assays by inhibiting coactivator recruitment. These data suggest that a balance of inductive Notch1 signals and inhibitory signals mediated through Deltex1 and other modulators regulate T-B lineage commitment.

Authors
Izon, DJ; Aster, JC; He, Y; Weng, A; Karnell, FG; Patriub, V; Xu, L; Bakkour, S; Rodriguez, C; Allman, D; Pear, WS
MLA Citation
Izon, DJ, Aster, JC, He, Y, Weng, A, Karnell, FG, Patriub, V, Xu, L, Bakkour, S, Rodriguez, C, Allman, D, and Pear, WS. "Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1." Immunity 16.2 (February 2002): 231-243.
PMID
11869684
Source
epmc
Published In
Immunity
Volume
16
Issue
2
Publish Date
2002
Start Page
231
End Page
243
DOI
10.1016/s1074-7613(02)00271-6
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