Warren S. Pear, M.D., Ph.D.
Associate Professor, Dept of Pathology and Laboratory Medicine
Abramson Family Cancer Research Institute
Institute for Medicine and Engineering

Cancer Biology Program

Address

421 Curie Blvd.
BRB II/III Rm. 611
Philadelphia, PA 19104

Office tel.: 215 573-7764
Lab tel.: (215) 746-6578
Fax: 215 573-6725
E-mail: wpear@mail.med.upenn.edu

Link(s)

Dr. Pear's Abramson Institute Page

EDUCATION

Williams College: BA (Economics), 1980.

Karolinska Institute; Stockholm, Sweden: Dr. Med. Sci. (Tumor Biology), 1987.

University of Rochester: MD (Medicine), 1989.

Brigham and Women's Hospital, Harvard Medical School: Residency (Pathology), 1989-1991.

Laboratory of David Baltimore; Rockefeller University and Massachusetts Institute of Technology: Postdoctoral Fellow, 1991-1996.

Research Interests

• Tumor Biology, Development, Stem Cells, Hematopoiesis

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

Search PubMed for articles

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.

Recent Publications

Maillard, I., Weng, A.P., Carpenter, A.C., Rodriguez, C.G., Sai, H., Xu, L., Allman, D., Aster, J.C., and Pear, W.S., Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 104, 1696-702, 2004.

Tu, L., Fang, T.C., Artis, D., Shestova, O., Pross, S., Maillard, I., Pear, W.S., Notch signaling is a critical regulator of type 2 immunity. J. Exp. Med., 8, 1037-1042: 2005.

McKay, P.Z., He, Y., Xu, L., Rodriguez, C.G., Karnell, F.G., Carpenter, A.C., Aster, J.C., Allman, D., and Pear, W.S., Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B cell malignancies. Blood 106, 3898-3906, 2005.

Weng, A.P., Millholland, J.M., Yashiro-Ohtani, Y., Arcangeli, M.L., Lau, A., Wai, C., del Bianco, C., Rodriguez, C.G., Sai, H., Tobias, J., Li, Y., Wolfe, M.S., Shachaf, C., Felsher, D., Blacklow, S.C., *Pear, W.S., *Aster, J.C., c-Myc is an important direct target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma. Genes Dev., 20, 2096-2109, 2006. *Corresponding Authors

Keeshan, K., He, Y., Wouters, B.J., Shestova, O., Xu, L., Sai, H., Rodriguez, C., Maillard, I., Tobias, J.W., Valk, P., Carroll, M., Aster, J.C. Delwel, R., and Pear, W.S., Tribbles homologue 2 (Trib2) inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell, 2006, in the press.

Lab

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:

Mark Chiang, Postdoctoral Fellow
Priya Dedhia, Graduate Student
Terry Fang, Graduate Student
Karen Keeshan, Postdoctoral Fellow
Ivan Maillard, Postdoctoral Fellow
Takuya Ohtani, Postdoctoral Fellow
Yumi Ohtani Postdoctoral Fellow
Hong Sai Research Specialist
Andras Schaffer, Postdoctoral Fellow
Olga Shestova Research Specialist
Maria Vega, PREP student
Lanwei Xu Research Specialist