Warren S. Pear

faculty photo
Gaylord P. and Mary Louise Harnwell Professor
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

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

Selected Publications

Severson E, Arnett KL, Wang H, Zang C, Taing L, Liu H, Pear WS, Liu XS, Blacklow SC, Aster JC: Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells. Science signaling 10(477), May 2017 Notes: No page number issued.

Plikus MV, Guerrero-Juarez CF, Ito M, Li YR, Dedhia PH, Zheng Y, Shao M, Gay DL, Ramos R, His TC, Oh JW, Wang X, Ramirez A, Konopelski SE, Elzein A, Wang A, Supapannachart RJ, Lee HL, Lim CH, Nace A, Guo A, Treffeisen E, Andl T, Ramirez RN, Murad R, Offermanns S, Metzger D, Chambon P, Widgerow AD, Tuan TL, Mortazavi A, Gupta RK, Hamilton BA, Millar SE, Seale P, Pear WS, Lazar MA, Cotsarelis G: Regeneration of fat cells from myofibroblasts during wound healing. Science 355(6326): 748-752, Feb 2017.

Aster JC, Pear WS, Blacklow SC: The Varied Roles of Notch in Cancer. Annual review of pathology 12: 245-275, Jan 2017.

Kobayashi M, Nabinger S, Bai Y, Yoshimoto M, Gao R, Chen S, Yao C, Dong Y, Zhang L, Rodriguez S, Yashiro-Ohtani Y, Pear WS, Carlesso N, Yoder MC, Kapur R, Kaplan MH, Lacorazza HD, Zhang ZY, Liu Y: Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals In Early T Cell Progenitors. Stem cells 35(4): 1053-1064, Dec 2016.

Chiang MY, Wang Q, Gormley AC, Stein SJ, Xu L, Shestova O, Aster JC, Pear WS: High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 128(18): 2229-2240, Nov 2016.

Greene M, Lai Y, Pajcini KV, Bailis W, Pear WS, Lancaster E: Delta/Notch-Like EGF-Related Receptor (DNER) Is Not a Notch Ligand. PloS one 11(9): e0161157, Sept 2016.

Uljon S, Xu X, Durzynska I, Stein S, Adelmant G, Marto JA, Pear WS, Blacklow SC: Structural Basis for Substrate Selectivity of the E3 Ligase COP1. Structure 24(5): 687-96, May 2016.

Stein SJ, Mack EA, Rome KS, Pajcini KV, Ohtani T, Xu L, Li Y, Meijerink JPP, Faryabi RB, Pear WS: Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL. PloS one 11(5): e0155408, May 2016.

Stein SJ, Mack EA, Rome KS, Pear WS: Tribbles in normal and malignant haematopoiesis. Biochemical Society transactions 43(5): 1112-5, 2015.

Kiss-Toth E, Velasco G, Pear WS: Tribbles at the cross-roads…. Biochemical Society transactions 43(5): 1049-50, 2015.

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Last updated: 08/04/2017
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