PEOPLE

Warren S. Pear, MD, PhD

Gaylord P. and Mary Louise Harnwell Professor
University of Pennsylvania School of Medicine

Contact Information556 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104-6160
Office: (215) 573-7764
Fax: (215) 573-6725

Email: wpear@mail.med.upenn.edu

Specialty Division

Precision and Computational Diagnostics, Immunobiology and Experimental Pathology

Research Expertise

Research Interests
Tumor Biology, Development, Stem Cells, Hematopoiesis, Immune Function

Research Techniques: In vivo and in vitro models of hematopoiesis, transformation and immunity, retroviral transduction, bone marrow transplantation, ES cell culture and differentiation, cDNA cloning, cell sorting, video microscopy, knockout and RNAi technology, ChIP-Seq and global transcription analysis

Description of Research
A major area of interest of this laboratory is understanding the processes that lead to the development and differentiation of mature hematopoietic cells from a single hematopoietic stem cell. We are particularly interested in studying the processes that perturb these normal processes and cause leukemia. A primary focus of the laboratory is the role that Notch proteins play in regulating hematopoietic cell fate decisions and cancer. Notch proteins are a conserved family of receptors that regulate cell fate decisions in organisms ranging from Drosophila to humans. Using a variety of in vitro and in vivo approaches, we have shown that Notch proteins are key regulators of multiple hematopoietic cell fates. These include establishment of the T cell lineage and helper type 2 T cells. We are presently undertaking studies to identify the signaling pathways that control these and other cell fate decisions in hematopoiesis. In addition to their role in normal hematopoiesis, dysregulation of Notch signaling is a cause of human leukemia. We have developed a mouse model of Notch-related leukemia and are using this to study the signaling pathways that lead to oncogenic transformation. Using gene array and bioinformatics approaches, we have identified several direct transcriptional targets of Notch signaling that appear to mediate its effects in normal development and leukemia. In addition, we are developing and testing ways to block Notch signaling that may be useful in treating leukemia and other Notch-dependent diseases.

Rotation Projects
1. Characterization of Notch transcriptional targets in hematopoiesis and leukemia. This project will characterize potential direct transcriptional targets of Notch signaling that we have identified in a microarray screen. The project will involve verifying that these are direct transcriptional targets using chromatin immunoprecipitation (ChIP), EMSA, and reporter assays and then testing whether these targets are functionally important using retroviral transduction, apoptosis, proliferation, and differentiation in both primary and established cell lines.

2. Identification of genes that potentiate Notch transforming activity. We have induced a number of Notch T cell leukemias using retroviruses that express activated forms of Notch1. The retroviral vectors also contain enhancer elements that can activate transcription of genes in the vicinity of their integration site. We have established techniques to rapidly clone the genes that are activated by retroviral vector integration and will use both in vitro and in vivo assays to determine if they synergize with Notch to induce leukemia.

3. We have identified Tribbles as a novel oncogene in acute myelogenous leukemia. Very little is know about Tribbles function. This project will use biochemical and functional assays to determine the function of Tribbles in leukemia and normal hematopoietic development.

Lab personnel:
Katherine Forsyth, Graduate Student
Ethan Mack, Graduate Student
Vicki Mercado, Post-baccalaureate Scholar
Caitlin O'Neill, Administrative Assistant
Yumi Ohtani, Senior Research Investigator
Jelena Petrovic, Postdoctoral Fellow
Kelly Rome, Graduate Student
Sarah Stein, Postdoctoral Fellow
Lanwei Xu, Research Specialist/Lab Manager

CVI Expertise

CVI Program Unit(s):
Cardiovascular Development / Congenital Heart Disease
Myocyte Biology / Heart Failure

CVI Research Description:
Notch signaling in cardiovascular development and homeostasis.

Itmat Expertise

blood cell development and transformation
Notch signaling

Graduate Groups

Cell and Molecular Biology
Immunology

Education

B.A. (Economics), Williams College, Williamstown, MA, 1980
Ph.D. (Tumor Biology - George Klein), Karolinska Institute, Stockholm, Sweden, 1987
M.D. University of Rochester, Rochester, NY, 1989

Specialty Certification

American Board of Clinical Pathology, 1996

Postgraduate Training

Intern in Pathology, Brigham and Women’s Hospital; Harvard Medical School, Boston MA, 1989-1990
Resident in Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, 1990-1991
Chief Resident, Laboratory Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, 1991-1991
Postdoctoral Fellow in laboratory of Professor David Baltimore, Rockefeller University, New York and Massachusetts Institute of Technology, Cambridge, MA, 1991-1996
Postdoctoral Fellowship for Physicians, Howard Hughes Medical Institute, 1992-1994
Special Fellow, Leukemia Society of America, 1995-1998

Awards and Honors

Phi Beta Kappa, 1980
Chief Resident, Laboratory Medicine, Brigham & Women's Hospital, 1991
Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians, 1992-1994
Young Investigator Award, American Society of Clinical Pathologists, 1994
Special Fellow of the Leukemia Society of America, 1995-1998
Penn/Hughes Scientist Award, Penn/Hughes Program in Developmental Biology, 1996-1998
Mary L. Smith Charitable Trust Award, 1997-1998
Scholar of the Leukemia and Lymphoma Society, 1998-2003
Wendy Will Case Cancer Fund Award, 1998-1999
John Morgan Society, University of Pennsylvania, 2002
Elected, American Society for Clinical Investigation (ASCI), 2002
Michael S. Brown Junior Faculty Research Award, University of Pennsylvania Medical School, 2002
Elected, Pluto Society (American Association of University Pathologists), 2003
Stohlman Scholar of the Leukemia and Lymphoma Society, 2003-2003
Gaylord P. and Mary Louise Harnwell Endowed Professorship, 2007-present
Elected, Association of American Physicians (AAP), 2011

Memberships and Professional Organizations

American Association for the Advancement of Science, 1995 - Present
American Society of Hematology, 1998 - Present
Leukemia and Lymphoma Society, Eastern Pennsylvania Chapter, 1998 - 2003
American Society of Clinical Investigation, 2002 - Present
Quinquinneal Review Site Visit at Cancer U.K., London, England, 2003 - 2003
Medical & Scientific Board of the Leukemia and Lymphoma Society, 2003 - 2010
NCI Site Review Team of Roth PO1-M.D. Anderson, Houston, TX, 2003 - 2003
Leukemia & Lymphoma Society Study Section, Translational Research Program, 2003 - 2009
Site Visit for National Cancer Institute of Canada, Toronto, Canada, 2004 - 2004
NCI Program Project Review, 2004 - 2004
American Society of Investigative Pathology, 2005 - Present
NIH Study Section, 2005 - Present
NIH Site Visit Review of Remy Bosselut, National Institutes of Health, Bethesda, MD, 2005 - 2005
American Association of Immunology, 2005 - Present
Thesis Opponent, Maria Gustafsson, Karolinska Institute, Stockholm, Sweden, 2007 - 2007
NIH Stem Cell PO1 Study Section, 2008 - 2008
NIH Site Visit Review of Jyoti Sen, National Institute of Aging,
Baltimore, MD, 2008 - 2012
Outside Thesis Examiner: Irina Matel, University of Toronto, Toronto, ON, Canada, 2009 - 2009
Site Visit for National Cancer Institute of Canada, Toronto, Canada, 2009 - 2009
Leukemia and Lymphoma Society of Canada (LLSC), 2013 - present
Leukemia and Lymphoma Society Career Development Award Study Section, 2013 - Present
Terry Fox Research Institute, 2014 - 2014
Cancer U.K. Expert Panel Review, London, 2014 - 2014

Web Links


Selected Publications

Notch dimerization is required for leukemogenesis and T cell development

Liu H, Chi WS, Chiang MY, Arnett KL, Xu L, Shestova O, Wang H, Li YM, Bhandoola A, Aster JC, Blacklow SC, Pear WS, Genes Dev. 24(): 2395-2407, 2010, PMID:20935071

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Differential ability of Tribbles family members to promote degradation of C/EBP{alpha} and induce acute myelogenous leukemia

Dedhia PH, Keeshan K, Uljon S, Xu L, Vega ME, Shestova O, Zaks-Zilberman M, Romany C, Blacklow SC, Pear WS, Blood 116(): 1321-8, 2010, PMID:20410507

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Pre-TCR signaling inactivates Notch1transcription by antagonizing E2A

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, Genes Dev. 23(): 1665-76, 2009, PMID:19605688

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Leukemia-associated Notch1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia

Chiang MY, Xu L, Shestova O, Histen G, L’Heureux S, Romany C, Childs ME, Gimotty PA, Aster JC, Pear WS, J Clin Invest. 118(): 3181-94, 2008, PMID:18677410

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Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells

Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS, Cell Stem Cell 2(): 356-66, 2008, PMID:18397755

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Notch signaling in leukemia

Aster JC, Pear WS, Blacklow SC, Annu Rev Pathol. 3(): 587-613, 2008, PMID:18039126

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Notch directly regulates Gata3 expression during T helper 2 cell differentiation

Fang TC, Ohtani Y, Del Bianco C, Knoblock D, Blacklow SC, Pear WS, Immunity 27(): 100-10, 2007, PMID:17658278

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Tribbles homologue 2 (Trib2) inactivates C/EBPalpha and causes acute myelogenous leukemia

Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez C, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS, Cancer Cell 10(): 401-11, 2006, PMID:17097562

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c-Myc is an important direct target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma

Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC, Genes Dev. 20(): 2096-109, 2006, PMID:16847353

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