You are here

Doan, Phuong Linh

Positions:

Assistant Professor of Medicine

Medicine, Hematological Malignancies
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2003

M.D. — University of North Carolina at Chapel Hill

Grants:

Role of ErbB receptor signaling in regulating normal and leukemic stem cell fate

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 09, 2014
End Date
August 31, 2019

Epidermal Growth Factor Regulates Leukemic Stem Cell Self-Renewal

Administered By
Medicine, Hematological Malignancies
AwardedBy
American Association for Cancer Research
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2016

Publications:

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.

The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.

Authors
Himburg, HA; Doan, PL; Quarmyne, M; Yan, X; Sasine, J; Zhao, L; Hancock, GV; Kan, J; Pohl, KA; Tran, E; Chao, NJ; Harris, JR; Chute, JP
MLA Citation
Himburg, HA, Doan, PL, Quarmyne, M, Yan, X, Sasine, J, Zhao, L, Hancock, GV, Kan, J, Pohl, KA, Tran, E, Chao, NJ, Harris, JR, and Chute, JP. "Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms." Nature medicine 23.1 (January 2017): 91-99.
PMID
27918563
Source
epmc
Published In
Nature Medicine
Volume
23
Issue
1
Publish Date
2017
Start Page
91
End Page
99
DOI
10.1038/nm.4251

Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10(m/+) mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10(+/+) mice. After total body irradiation (TBI), Grb10(m/+) mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10(+/+) mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

Authors
Yan, X; Himburg, HA; Pohl, K; Quarmyne, M; Tran, E; Zhang, Y; Fang, T; Kan, J; Chao, NJ; Zhao, L; Doan, PL; Chute, JP
MLA Citation
Yan, X, Himburg, HA, Pohl, K, Quarmyne, M, Tran, E, Zhang, Y, Fang, T, Kan, J, Chao, NJ, Zhao, L, Doan, PL, and Chute, JP. "Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration." Cell reports 17.6 (November 2016): 1584-1594.
PMID
27806297
Source
epmc
Published In
Cell Reports
Volume
17
Issue
6
Publish Date
2016
Start Page
1584
End Page
1594
DOI
10.1016/j.celrep.2016.10.025

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal and Regeneration Via Control of mTOR Signaling

Authors
Chute, JP; Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Tran, E; Chao, NJ; Zhao, L
MLA Citation
Chute, JP, Yan, X, Himburg, HA, Doan, PL, Quarmyne, M, Tran, E, Chao, NJ, and Zhao, L. "Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal and Regeneration Via Control of mTOR Signaling." March 2016.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
22
Issue
3
Publish Date
2016
Start Page
S426
End Page
S426

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling

Authors
Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Tran, E; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Yan, X, Himburg, HA, Doan, PL, Quarmyne, M, Tran, E, Zhao, L, Chao, NJ, and Chute, JP. "Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Dickkopf 1 (Dkk1) Regulates Hematopoietic Stem Cell Regeneration

Authors
Himburg, HA; Doan, PL; Yan, X; Quarmyne, M; Zhao, L; Tran, E; Chao, NJ; Harris, J; Chute, JP
MLA Citation
Himburg, HA, Doan, PL, Yan, X, Quarmyne, M, Zhao, L, Tran, E, Chao, NJ, Harris, J, and Chute, JP. "Dickkopf 1 (Dkk1) Regulates Hematopoietic Stem Cell Regeneration." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.

Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area-forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34⁺CD38⁻CD45RA⁻lin⁻ PTPσ⁻ cells substantially increased the repopulating capacity of human HSCs compared with CD34⁺CD38⁻CD45RA⁻lin⁻ cells and CD34⁺CD38⁻CD45RA⁻lin⁻PTPσ⁺ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.

Authors
Quarmyne, M; Doan, PL; Himburg, HA; Yan, X; Nakamura, M; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Quarmyne, M, Doan, PL, Himburg, HA, Yan, X, Nakamura, M, Zhao, L, Chao, NJ, and Chute, JP. "Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity." The Journal of clinical investigation 125.1 (January 2015): 177-182.
PMID
25415437
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
1
Publish Date
2015
Start Page
177
End Page
182
DOI
10.1172/jci77866

Protein Tyrosine Phosphatase-Sigma (PTP sigma) Regulates Hematopoietic Stem Cell Repopulating Capacity

Authors
Quarmyne, M; Doan, PL; Himburg, HA; Yan, X; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Quarmyne, M, Doan, PL, Himburg, HA, Yan, X, Zhao, L, Chao, NJ, and Chute, JP. "Protein Tyrosine Phosphatase-Sigma (PTP sigma) Regulates Hematopoietic Stem Cell Repopulating Capacity." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell Renewal

Authors
Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Chao, NJ; Chute, JP
MLA Citation
Yan, X, Himburg, HA, Doan, PL, Quarmyne, M, Chao, NJ, and Chute, JP. "Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell Renewal." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Calcium Calmodulin Dependent Kinase Kinase 2 Regulates Hematopoietic Stem Cell Regeneration and Quiescence

Authors
Lento, W; Huang, W; Doan, P; Chao, NJ; Racioppi, L
MLA Citation
Lento, W, Huang, W, Doan, P, Chao, NJ, and Racioppi, L. "Calcium Calmodulin Dependent Kinase Kinase 2 Regulates Hematopoietic Stem Cell Regeneration and Quiescence." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.

Authors
Himburg, HA; Yan, X; Doan, PL; Quarmyne, M; Micewicz, E; McBride, W; Chao, NJ; Slamon, DJ; Chute, JP
MLA Citation
Himburg, HA, Yan, X, Doan, PL, Quarmyne, M, Micewicz, E, McBride, W, Chao, NJ, Slamon, DJ, and Chute, JP. "Pleiotrophin mediates hematopoietic regeneration via activation of RAS." The Journal of clinical investigation 124.11 (November 2014): 4753-4758.
PMID
25250571
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
11
Publish Date
2014
Start Page
4753
End Page
4758
DOI
10.1172/jci76838

Ex vivo expansion of murine and human hematopoietic stem cells.

Hematopoietic stem cells have the capacity to self-renew and give rise to the entirety of the mature blood and immune system throughout the lifespan of an organism. Here, we describe methods to isolate and culture murine bone marrow (BM) CD34(-)ckit(+)Sca1(+)Lineage(-) (CD34(-)KSL) hematopoietic stem cells (HSCs). We also describe a method to measure functional HSC content via the competitive repopulation assay. Furthermore, we summarize methods to isolate and culture human CD34(+)CD38(-)Lineage(-) cells which are enriched for human hematopoietic stem and progenitor cells.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, PL, and Chute, JP. "Ex vivo expansion of murine and human hematopoietic stem cells." Methods in molecular biology (Clifton, N.J.) 1185 (January 2014): 211-221.
PMID
25062631
Source
epmc
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1185
Publish Date
2014
Start Page
211
End Page
221
DOI
10.1007/978-1-4939-1133-2_14

Ex vivo expansion of murine and human hematopoietic stem cells

Hematopoietic stem cells have the capacity to self-renew and give rise to the entirety of the mature blood and immune system throughout the lifespan of an organism. Here, we describe methods to isolate and culture murine bone marrow (BM) CD34-ckit+Sca1+Lineage- (CD34-KSL) hematopoietic stem cells (HSCs). We also describe a method to measure functional HSC content via the competitive repopulation assay. Furthermore, we summarize methods to isolate and culture human CD34 +CD38-Lineage- cells which are enriched for human hematopoietic stem and progenitor cells. © 2014 Springer Science+Business Media New York.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, PL, and Chute, JP. "Ex vivo expansion of murine and human hematopoietic stem cells." Methods in Molecular Biology 1185 (2014): 211-221.
Source
scopus
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1185
Publish Date
2014
Start Page
211
End Page
221
DOI
10.1007/978-1-4939-1133-2-14

Epidermal growth factor regulates hematopoietic regeneration after radiation injury.

The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.

Authors
Doan, PL; Himburg, HA; Helms, K; Russell, JL; Fixsen, E; Quarmyne, M; Harris, JR; Deoliviera, D; Sullivan, JM; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Himburg, HA, Helms, K, Russell, JL, Fixsen, E, Quarmyne, M, Harris, JR, Deoliviera, D, Sullivan, JM, Chao, NJ, Kirsch, DG, and Chute, JP. "Epidermal growth factor regulates hematopoietic regeneration after radiation injury." Nat Med 19.3 (March 2013): 295-304.
PMID
23377280
Source
pubmed
Published In
Nature Medicine
Volume
19
Issue
3
Publish Date
2013
Start Page
295
End Page
304
DOI
10.1038/nm.3070

Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury.

Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we used genetic models to determine whether radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM vasculature, and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Harris, JR; Lucas, J; Holshausen, KC; Meadows, SK; Daher, P; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Himburg, HA, Helms, K, Harris, JR, Lucas, J, Holshausen, KC, Meadows, SK, Daher, P, Jeffords, LB, Chao, NJ, Kirsch, DG, and Chute, JP. "Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury." Stem Cells 31.2 (February 2013): 327-337.
PMID
23132593
Source
pubmed
Published In
Stem Cells
Volume
31
Issue
2
Publish Date
2013
Start Page
327
End Page
337
DOI
10.1002/stem.1275

Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche.

The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, HA, Harris, JR, Ito, T, Daher, P, Russell, JL, Quarmyne, M, Doan, PL, Helms, K, Nakamura, M, Fixsen, E, Herradon, G, Reya, T, Chao, NJ, Harroch, S, and Chute, JP. "Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche." Cell Rep 2.4 (October 25, 2012): 964-975.
PMID
23084748
Source
pubmed
Published In
Cell Reports
Volume
2
Issue
4
Publish Date
2012
Start Page
964
End Page
975
DOI
10.1016/j.celrep.2012.09.002

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma.

BACKGROUND: Embolizing branches of the hepatic artery lengthens survival for patients with unresectable hepatocellular carcinoma (HCC), but the benefit of combining chemotherapy with the embolizing particles remains controversial. METHODS: A retrospective review was undertaken of sequential patients with advanced HCC undergoing embolization in the past 10 years at 2 neighboring institutions and with 2 years of follow-up data. TACE was generally performed with doxorubicin plus mitomycin C. RESULTS: One hundred twenty-four patients were included; 77 received TACE and 47 received TAE. On multivariable analysis stratified by institution, type of embolization and CLIP score significantly predicted PFS and time to progression (TTP), whereas CLIP score and AFP independently predicted overall survival (OS). TACE significantly prolonged PFS and TTP (P = .0004 and P = .001, respectively), but not OS (P = .83). CONCLUSIONS: The addition of chemotherapy to TAE prolongs PFS and TTP. Future efforts should focus on adjunctive therapies after the embolization to increase survival.

Authors
Morse, MA; Hanks, BA; Suhocki, P; Doan, PL; Liu, EA; Frost, P; Bernard, SA; Tsai, A; Moore, DT; O'Neil, BH
MLA Citation
Morse, MA, Hanks, BA, Suhocki, P, Doan, PL, Liu, EA, Frost, P, Bernard, SA, Tsai, A, Moore, DT, and O'Neil, BH. "Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma." Clin Colorectal Cancer 11.3 (September 2012): 185-190.
PMID
22280845
Source
pubmed
Published In
Clinical colorectal cancer
Volume
11
Issue
3
Publish Date
2012
Start Page
185
End Page
190
DOI
10.1016/j.clcc.2011.11.003

EGF SIGNALING REGULATES HEMATOPOIETIC REGENERATION FOLLOWING TOTAL BODY IRRADIATION

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Sullivan, JM; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Himburg, HA, Helms, K, Sullivan, JM, Jeffords, LB, Chao, NJ, Kirsch, DG, and Chute, JP. "EGF SIGNALING REGULATES HEMATOPOIETIC REGENERATION FOLLOWING TOTAL BODY IRRADIATION." February 2012.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S235
End Page
S235

PLEIOTROPHIN REGULATES NORMAL AND LEUKEMIC HEMATOPOIETIC STEM CELL FATE

Authors
Himburg, HA; Ito, T; Harris, JR; Quarmyne, M; Helms, KL; Doan, PL; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Ito, T, Harris, JR, Quarmyne, M, Helms, KL, Doan, PL, Reya, T, Chao, NJ, and Chute, JP. "PLEIOTROPHIN REGULATES NORMAL AND LEUKEMIC HEMATOPOIETIC STEM CELL FATE." February 2012.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S236
End Page
S236

The vascular niche: home for normal and malignant hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are uniquely capable of self-renewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niches' wherein HSCs reside. HSCs have been shown to reside in close association with bone marrow (BM) osteoblasts in the endosteal niche and also in proximity to BM sinusoidal vessels. An unresolved question surrounds whether the endosteal and vascular niches provide synchronous or redundant regulation of HSC fate or whether these niches provide wholly unique regulatory functions. Furthermore, while some aspects of the mechanisms through which osteoblasts regulate HSC fate have been defined, the mechanisms through which the vascular niche regulates HSC fate remain obscure. Here, we summarize the anatomic and functional basis supporting the concept of an HSC vascular niche as well as the precise function of endothelial cells, perivascular cells and stromal cells within the niche in regulating HSC fate. Lastly, we will highlight the role of the vascular niche in regulating leukemic stem cell fate in vivo.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, PL, and Chute, JP. "The vascular niche: home for normal and malignant hematopoietic stem cells." Leukemia 26.1 (January 2012): 54-62. (Review)
PMID
21886170
Source
pubmed
Published In
Leukemia
Volume
26
Issue
1
Publish Date
2012
Start Page
54
End Page
62
DOI
10.1038/leu.2011.236

Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, HA, Harris, JR, Ito, T, Daher, P, Russell, JL, Quarmyne, M, Doan, PL, Helms, K, Nakamura, M, Fixsen, E, Herradon, G, Reya, T, Chao, NJ, Harroch, S, and Chute, JP. "Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche." Cell Reports 2.6 (2012): 1774--.
Source
scival
Published In
Cell Reports
Volume
2
Issue
6
Publish Date
2012
Start Page
1774-
DOI
10.1016/j.celrep.2012.11.005

High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation

Authors
Gasparetto, C; Bacon, WA; Doan, P; Rizzieri, DA; Horwitz, ME; Chute, JP; Sullivan, KM; Yopp, A; Li, Z; Chao, NJ; Long, GD
MLA Citation
Gasparetto, C, Bacon, WA, Doan, P, Rizzieri, DA, Horwitz, ME, Chute, JP, Sullivan, KM, Yopp, A, Li, Z, Chao, NJ, and Long, GD. "High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
879
End Page
879

TIE2(+) ENDOTHELIAL CELLS MEDIATE HEMATOPOIETIC STEM CELL REGENERATION VIA EGF SIGNALING

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Meadows, SK; Daher, P; Sullivan, JM; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Himburg, HA, Helms, K, Meadows, SK, Daher, P, Sullivan, JM, Jeffords, LB, Chao, NJ, Kirsch, DG, and Chute, JP. "TIE2(+) ENDOTHELIAL CELLS MEDIATE HEMATOPOIETIC STEM CELL REGENERATION VIA EGF SIGNALING." February 2011.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
2
Publish Date
2011
Start Page
S188
End Page
S188
DOI
10.1016/j.bbmt.2010.12.107

Pleiotrophin Signaling Is Necessary for Hematopoietic Stem Cell Self Renewal and Is Regulated by the Bone Marrow Microenvironment

Authors
Himburg, HA; Daher, P; Russell, L; Doan, P; Quarmyne, M; Meadows, S; Herradon, G; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Daher, P, Russell, L, Doan, P, Quarmyne, M, Meadows, S, Herradon, G, Chao, NJ, and Chute, JP. "Pleiotrophin Signaling Is Necessary for Hematopoietic Stem Cell Self Renewal and Is Regulated by the Bone Marrow Microenvironment." February 2011.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
2
Publish Date
2011
Start Page
S149
End Page
S149
DOI
10.1016/j.bbmt.2010.12.002

VE Cadherin Positive Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo

Authors
Russell, JL; Doan, P; Himburg, HA; Meadows, SK; Daher, P; Helms, K; Quarmyne, M; Chao, NJ; Kirsch, D; Chute, JP
MLA Citation
Russell, JL, Doan, P, Himburg, HA, Meadows, SK, Daher, P, Helms, K, Quarmyne, M, Chao, NJ, Kirsch, D, and Chute, JP. "VE Cadherin Positive Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1532
End Page
1532

Pleiotrophin Signaling Is Necessary and Sufficient for Hematopoietic Stem Cell Self-Renewal In Vivo

Authors
Himburg, HA; Daher, P; Russell, JL; Doan, P; Quarmyne, M; Meadows, SK; Helms, K; Herradon, G; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Daher, P, Russell, JL, Doan, P, Quarmyne, M, Meadows, SK, Helms, K, Herradon, G, Chao, NJ, and Chute, JP. "Pleiotrophin Signaling Is Necessary and Sufficient for Hematopoietic Stem Cell Self-Renewal In Vivo." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
180
End Page
180

Facilitation of Hematopoietic Reconstitution Via Inhibition of Bone Marrow Endothelial Cell-Mediated SDF-1 Signaling

Authors
Doan, PL; Russell, JL; Himburg, HA; Meadows, SK; Daher, P; Helms, K; Quarmyne, M; Harris, JR; Reya, T; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Himburg, HA, Meadows, SK, Daher, P, Helms, K, Quarmyne, M, Harris, JR, Reya, T, Chao, NJ, Kirsch, DG, and Chute, JP. "Facilitation of Hematopoietic Reconstitution Via Inhibition of Bone Marrow Endothelial Cell-Mediated SDF-1 Signaling." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1578
End Page
1578

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Authors
Meadows, SK; Dressman, HK; Daher, P; Himburg, H; Russell, JL; Doan, P; Chao, NJ; Lucas, J; Nevins, JR; Chute, JP
MLA Citation
Meadows, SK, Dressman, HK, Daher, P, Himburg, H, Russell, JL, Doan, P, Chao, NJ, Lucas, J, Nevins, JR, and Chute, JP. "Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles. (Published online)" PLoS One 5.7 (July 12, 2010): e11535-.
Website
http://hdl.handle.net/10161/4550
PMID
20634956
Source
pubmed
Published In
PloS one
Volume
5
Issue
7
Publish Date
2010
Start Page
e11535
DOI
10.1371/journal.pone.0011535

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells.

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

Authors
Himburg, HA; Muramoto, GG; Daher, P; Meadows, SK; Russell, JL; Doan, P; Chi, J-T; Salter, AB; Lento, WE; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Muramoto, GG, Daher, P, Meadows, SK, Russell, JL, Doan, P, Chi, J-T, Salter, AB, Lento, WE, Reya, T, Chao, NJ, and Chute, JP. "Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells." Nat Med 16.4 (April 2010): 475-482.
PMID
20305662
Source
pubmed
Published In
Nature Medicine
Volume
16
Issue
4
Publish Date
2010
Start Page
475
End Page
482
DOI
10.1038/nm.2119

Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34(-)c-kit(+)Sca-1(+)lineage(-) (34(-)KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34(-)KSL cells. Treatment of bone marrow (BM) 34(-)KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.

Authors
Muramoto, GG; Russell, JL; Safi, R; Salter, AB; Himburg, HA; Daher, P; Meadows, SK; Doan, P; Storms, RW; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
Muramoto, GG, Russell, JL, Safi, R, Salter, AB, Himburg, HA, Daher, P, Meadows, SK, Doan, P, Storms, RW, Chao, NJ, McDonnell, DP, and Chute, JP. "Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity." Stem Cells 28.3 (March 31, 2010): 523-534.
PMID
20054864
Source
pubmed
Published In
Stem Cells
Volume
28
Issue
3
Publish Date
2010
Start Page
523
End Page
534
DOI
10.1002/stem.299

Long Term Survival Following High-dose Sequential Therapy with Autologous Hematopoietic Cell Rescue for Multiple Myeloma

High-dose therapy (HDT) with autologous hematopoietic cell rescue (AHCR) improves survival in patients with multiple myeloma, but is not curative due to a continuous risk of relapse. One approach to try to reduce relapse is to optimize the pretransplant therapy and preparative regimen. We investigated the outcome of sequential HDT with AHCR. Patients were initially treated with standard dose chemotherapy (primarily VAD) to maximum response. They then received cyclophosphamide 4 gm/m2 followed by G-CSF and peripheral blood hematopoietic cell collection by apheresis upon count recovery. They were then treated with etoposide 2 gm/m2 followed by G-CSF and apheresis upon count recovery. The transplant preparative regimen consisted of carmustine 500 mg/m2 on day -4 and melphalan 200 mg/m2 on day -2 followed by AHCR on day 0. Seventy-seven patients were enrolled between 1997 and 2001. Patients were eligible for enrollment if they had a confirmed diagnosis of multiple myeloma at the transplant center, had received multi-agent based chemotherapy for cytoreduction, and had no serious comorbidities. The patient population included 56% men with a median age at transplant of 54 years (range 39-68 years). Thirty-eight patients had IgG myeloma, 14 patients had IgA myeloma, 8 patients had light chain only disease, 4 patients had nonsecretory disease and subtype is unknown in six patients. The median progression-free survival was 3.9 years [CI 2.7-6.0 years] with a median overall survival of 9.5 years (CI 4.7-11 years). The median follow up of the 36 surviving patients is 8.43 years with a range of 4.71 to 11.09 years. One patient was lost to follow up. The Kaplan-Meir estimated progression-free survival at 10 years is 35% with overall survival of 45%. One patient developed secondary acute myeloid leukemia and one patient developed secondary myelodysplastic syndrome. High dose sequential therapy results in long term survival in a significant proportion of patients with multiple myeloma.

Authors
Doan, PL; Chute, JP; Gasparetto, C; Horwitz, M; Rizzieri, D; Smith, C; Sullivan, K; Edwards, J; Jacobson, R; Corbett, K; Chao, N; Long, G
MLA Citation
Doan, PL, Chute, JP, Gasparetto, C, Horwitz, M, Rizzieri, D, Smith, C, Sullivan, K, Edwards, J, Jacobson, R, Corbett, K, Chao, N, and Long, G. "Long Term Survival Following High-dose Sequential Therapy with Autologous Hematopoietic Cell Rescue for Multiple Myeloma." American Society of Blood and Marrow Transplantation. 2010.
Source
manual
Volume
16
Issue
2
Publish Date
2010
Start Page
S201
End Page
S201

Advances in cord blood transplants in adults

Umbilical cord blood is an acceptable source of hematopoietic stem cells for patients with malignant diseases but has limitations in its use. In this review, we will discuss these limitations and the recent advances in cord blood transplants that may enable cord blood to become more widely available as an alternative stem cell source for adults for the treatment of malignant diseases and for use in regenerative medicine. © 2010 Medicine Reports Ltd.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "Advances in cord blood transplants in adults." F1000 Medicine Reports 2.1 (2010).
PMID
20948874
Source
scival
Published In
F1000 Medicine Reports
Volume
2
Issue
1
Publish Date
2010
DOI
10.3410/M2-12

Systemic Administration of Pleiotrophin Induces Hematopoietic Stem Cell Regeneration In Vivo

Authors
Himburg, HA; Daher, P; Meadows, SK; Russell, JL; Doan, P; Muramoto, G; Chao, NJ; Chute, J
MLA Citation
Himburg, HA, Daher, P, Meadows, SK, Russell, JL, Doan, P, Muramoto, G, Chao, NJ, and Chute, J. "Systemic Administration of Pleiotrophin Induces Hematopoietic Stem Cell Regeneration In Vivo." November 20, 2009.
Source
wos-lite
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
602
End Page
602

Deletion of Bak and Bax in Tie2+BM Hematopoietic Stem Cells Induces a B Cell Lymphoproliferative Disorder

Authors
Doan, PL; Russell, JL; Meadows, SK; Himburg, HA; Daher, P; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Meadows, SK, Himburg, HA, Daher, P, Chao, NJ, Kirsch, DG, and Chute, JP. "Deletion of Bak and Bax in Tie2+BM Hematopoietic Stem Cells Induces a B Cell Lymphoproliferative Disorder." November 20, 2009.
Source
wos-lite
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
513
End Page
513

Tie2+Bone Marrow Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo

Authors
Doan, PL; Russell, JL; Meadows, SK; Himburg, HA; Daher, P; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Meadows, SK, Himburg, HA, Daher, P, Chao, NJ, Kirsch, DG, and Chute, JP. "Tie2+Bone Marrow Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo." November 20, 2009.
Source
wos-lite
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
106
End Page
106

The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation causes significant morbidity and mortality. An important site of GVHD is the gastrointestinal (GI) tract because development of acute GI GVHD is prognostic of overall survival. The standard of care to treat acute GI GVHD is systemic corticosteroids and immunosuppressants; however, the use of these therapies can cause life-threatening opportunistic infections. To limit the adverse effects of systemic immunosuppression, the topically active corticosteroid beclometasone dipropionate has been investigated in case studies and in randomized placebo-controlled trials for the treatment of acute GI GVHD. In this review, we appraise these studies with beclometasone dipropionate, and discuss future randomized studies to clarify the role of beclometasone dipropionate for the treatment and prevention of acute GVHD. At present, more data are required before the addition of beclometasone dipropionate to systemic corticosteroids for the treatment of acute GVHD can be considered the standard of care.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease." Drugs 69.10 (July 9, 2009): 1339-1350. (Review)
PMID
19583452
Source
pubmed
Published In
Drugs
Volume
69
Issue
10
Publish Date
2009
Start Page
1339
End Page
1350
DOI
10.2165/00003495-200969100-00004

Umbilical cord blood: biology and transplantation.

Umbilical cord blood transplantation is becoming an acceptable alternative source of hematopoietic stem cells for patients with malignant diseases. Cord blood differs from bone marrow and peripheral blood progenitors in its immune tolerance and kinetics of engraftment. In this article, we will review the biology of cord blood stem cells and clinical studies of cord blood transplants in pediatric and adult populations. We will also discuss potential uses of cord blood stem cells in regenerative medicine and novel methods for ex vivo expansion of hematopoietic stem cells. As we learn more about cord blood transplants, there is the potential to overcome the limitations of cord blood transplants so that they can become more widely available.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "Umbilical cord blood: biology and transplantation." Expert Rev Hematol 2.2 (April 2009): 197-208. (Review)
PMID
21083452
Source
pubmed
Published In
Expert Review of Hematology
Volume
2
Issue
2
Publish Date
2009
Start Page
197
End Page
208
DOI
10.1586/ehm.09.9

Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti-VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non-EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.

Authors
Salter, AB; Meadows, SK; Muramoto, GG; Himburg, H; Doan, P; Daher, P; Russell, L; Chen, B; Chao, NJ; Chute, JP
MLA Citation
Salter, AB, Meadows, SK, Muramoto, GG, Himburg, H, Doan, P, Daher, P, Russell, L, Chen, B, Chao, NJ, and Chute, JP. "Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo." Blood 113.9 (February 26, 2009): 2104-2107.
PMID
19141867
Source
pubmed
Published In
Blood
Volume
113
Issue
9
Publish Date
2009
Start Page
2104
End Page
2107
DOI
10.1182/blood-2008-06-162941

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

Authors
Safi, R; Muramoto, GG; Salter, AB; Meadows, S; Himburg, H; Russell, L; Daher, P; Doan, P; Leibowitz, MD; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
Safi, R, Muramoto, GG, Salter, AB, Meadows, S, Himburg, H, Russell, L, Daher, P, Doan, P, Leibowitz, MD, Chao, NJ, McDonnell, DP, and Chute, JP. "Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture." Mol Endocrinol 23.2 (February 2009): 188-201.
PMID
19106195
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
23
Issue
2
Publish Date
2009
Start Page
188
End Page
201
DOI
10.1210/me.2008-0121

Predictors of survival in patients with hepatocellular carcinoma treated with transarterial chemoembolization

Authors
Doan, PL; O'Neil, BH; Moore, DT; Bernard, SA
MLA Citation
Doan, PL, O'Neil, BH, Moore, DT, and Bernard, SA. "Predictors of survival in patients with hepatocellular carcinoma treated with transarterial chemoembolization." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)

Authors
Hanks, BA; Suhocki, PV; DeLong, DM; Doan, PL; Liu, E; Tsai, AL; Burke, CT; Bernard, SA; O'Neil, BH; Morse, MA
MLA Citation
Hanks, BA, Suhocki, PV, DeLong, DM, Doan, PL, Liu, E, Tsai, AL, Burke, CT, Bernard, SA, O'Neil, BH, and Morse, MA. "The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Abdominal varices caused by chronic Budd-Chiari syndrome

Authors
Dellon, ES; Doan, PL; Batey, BM
MLA Citation
Dellon, ES, Doan, PL, and Batey, BM. "Abdominal varices caused by chronic Budd-Chiari syndrome." Clinical Gastroenterology and Hepatology 4.3 (2006): xxiv-.
Source
scival
Published In
Clinical Gastroenterology and Hepatology
Volume
4
Issue
3
Publish Date
2006
Start Page
xxiv
DOI
10.1016/S1542-3565(05)00862-1

Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not.

Recombination hotspots have previously been discovered in bacteriophage T4 by two different approaches, marker rescue recombination from heavily damaged phage genomes and recombination during co-infection by two undamaged phage genomes. The phage replication origin ori(34) is located in a region that has a hotspot in both assays. To determine the relationship between the origin and the two kinds of hotspots, we generated phage carrying point mutations that should inactivate ori(34) but not affect the gene 34 reading frame (within which ori(34) is located). The mutations eliminated the function of the origin, as judged by both autonomous replication of plasmids during T4 infection and two-dimensional gel analysis of phage genomic replication intermediates. As expected from past studies, the ori(34) mutations also eliminated the hotspot for marker rescue recombination from UV-irradiated genomes. However, the origin mutations had no effect on the recombination hotspot that is observed with co-infecting undamaged phage genomes, demonstrating that some DNA sequence other than the origin is responsible for inflated recombination between undamaged genomes. The hotspots for marker rescue recombination may result from a replication fork restart process that acts upon origin-initiated replication forks that become blocked at nearby DNA damage. The two-dimensional gel analysis also revealed phage T4 replication intermediates not previously detected by this method, including origin theta forms.

Authors
Doan, PL; Belanger, KG; Kreuzer, KN
MLA Citation
Doan, PL, Belanger, KG, and Kreuzer, KN. "Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not." Genetics 157.3 (March 2001): 1077-1087.
PMID
11238396
Source
pubmed
Published In
Genetics
Volume
157
Issue
3
Publish Date
2001
Start Page
1077
End Page
1087
Show More

Research Areas:

  • Antineoplastic Agents
  • Bone Marrow
  • Endothelial Cells
  • Epidermal Growth Factor
  • Gene Expression
  • Hematologic Neoplasms
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Radiation Injuries, Experimental
  • Radiation, Ionizing
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Epidermal Growth Factor
  • Regeneration
  • Stem Cell Niche