Warren S. Pear

faculty photo
Gaylord P. and Mary Louise Harnwell Professor of Pathology and Laboratory Medicine
Abramson Cancer Center Member, University of Pennsylvania
Attending Physician, Molecular Pathology, Hospital of the University of Pennsylvania
Associate Member Abramson Family Cancer Research Institute, University of Pennsylvania
Institute for Immunology, Executive Committee, University of Pennsylvania
Co-Program Leader, Cancer Immunology, Abramson Cancer Center, University of Pennsylvania
Co-Director, Research Residency Program, Dept of Pathology & Laboratory Medicine, Hospital of the University of Pennsylvania
Director, Immunopathology Division, Dept of Pathology & Lab Medicine, University of Pennsylvania
Department: Pathology and Laboratory Medicine

Contact information
556 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104-6160
Office: (215) 573-7764
Fax: (215) 573-6725
Graduate Group Affiliations
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.
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Description of 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 for 2010
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:
Will Bailis, Graduate Student
Caitlin O'Neill, Administrative Assistant
Yumi Ohtani, Senior Research Investigator
Kosta Pajcini, Postdoctoral Fellow
Kelly Rome, Graduate Student
Sarah Stein, Postdoctoral Fellow
Lanwei Xu, Research Specialist/Lab Manager
Shuqian Yu, Research Specialist

Description of Itmat Expertise

blood cell development and transformation
Notch signaling

Selected Publications

Liu H, Chi WS, Chiang MY, Arnett KL, Xu L, Shestova O, Wang H, Li YM, Bhandoola A, Aster JC, Blacklow SC, Pear WS: Notch dimerization is required for leukemogenesis and T cell development. Genes Dev. 24: 2395-2407, 2010.

Dedhia PH, Keeshan K, Uljon S, Xu L, Vega ME, Shestova O, Zaks-Zilberman M, Romany C, Blacklow SC, Pear WS: Differential ability of Tribbles family members to promote degradation of C/EBP{alpha} and induce acute myelogenous leukemia. Blood 116: 1321-8, 2010.

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: Pre-TCR signaling inactivates Notch1transcription by antagonizing E2A. Genes Dev. 23: 1665-76, 2009.

Chiang MY, Xu L, Shestova O, Histen G, L’Heureux S, Romany C, Childs ME, Gimotty PA, Aster JC, Pear WS: Leukemia-associated Notch1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest. 118: 3181-94, 2008.

Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS: Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2: 356-66, 2008.

Aster JC, Pear WS, Blacklow SC: Notch signaling in leukemia. Annu Rev Pathol. 3: 587-613, 2008.

Fang TC, Ohtani Y, Del Bianco C, Knoblock D, Blacklow SC, Pear WS: Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27: 100-10, 2007.

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: Tribbles homologue 2 (Trib2) inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell 10: 401-11, 2006.

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: c-Myc is an important direct target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20: 2096-109, 2006.

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Last updated: 08/26/2014
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