Immunology Graduate Group
Warren S. Pear, M.D., Ph.D.
Associate Professor
Department of Pathology and Institute for Medicine and Engineering
Address: 611 Biomedical Research Building II/III/6160
Office Phone: (215) 573-7764
Lab Phone: (215) 573-6016
Email: wpear@mail.med.upenn.edu
Education:
B.A., Williams College, MA
M.D., University of Rochester, NY
Ph.D., Tumor Biology, Karolinska Institute, Stockholm, Sweden
Post Doctoral Fellow, Massachusetts Institute of Technology
Research Interests
Hematopoietic Development and Transformation
Resarch Summary
A major area of interest of this laboratory is understanding the developmental processes that lead to the development and differentiation of hematopoietic cells from stem cells. A primary focus of the laboratory is the role that Notch proteins play in regulating hematopoietic cell fate decisions. Notch proteins are a conserved family of receptors that regulate cell fate decisions in organisms ranging from Drosophila to humans. Because hematopoietic development requires a number of cell fate decisions to generate mature cells from a single hematopoietic stem cell, Notch proteins are likely to control some of these developmental switches. Using a variety of in vitro and in vivo approaches, we have shown that Notch proteins regulate the developmental decision of how a common lymphoid progenitor cell becomes either a B-cell or a T-cell. 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, Notch proteins have also been implicated in 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. A second area of research in the lab is understanding the role of the bcr/abl oncogene in causing chronic myelogenous leukemia, a leukemia that originates in the hematopoietic stem cell. We are using a combination of biochemical, cell culture, and in vivo assays to understand how the bcr/abl fusion protein causes leukemia.
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| Notch signaling drives T cell development and blocks B cell development from a common lymphoid progenitor. |
Selected Publications
Pui, J.C., Allman, D., Xu, L., DeRocco, S., Karnell, F.G., Bakkour, S., Lee, J.Y., Kadesch, T., Hardy, R.R., Aster, J.C., and Pear, W.S.: Notch1 expression in early lymphopoiesis influences B versus T lineage determination, Immunity, 299-308, 1999.
Aster, J.C., Xu, L., Karnell, F.G., Patriub, V., Pui, J.C., and Pear, W.S.: Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by Notch1, Mol. Cell. Biol.13, 73-84, 2000.
Varnum-Finney, B, Xu, L, Brashem-Stein, C., Nourigat, C., Flowers, D., Bakkour, S., Pear, W.S., and Bernstein, I.D.: Pluripotent, cytokine dependent, hematopoietic cells are immortalized by constitutive Notch1 signaling, Nature Medicine 6, 1278-1281, 2000.
Izon, D.J., Punt, J.A., Xu, L., Karnell, F.G., Allman, D., Myung, P.S., Boerth, N.J., Pui, J.C., Koretzky, G.A., and Pear, W.S., Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength, Immunity 14, 253-64, 2001.
Allman, D.M., Karnell, F.G., Bakkour, S., Xu, L., Punt, J.A., Koretzky, G.A., Pui, J.C., Aster, J.C., and Pear, W.S., Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells, J. Exp. Med., 194, 99-106, 2001.
Izon, D.J., Aster, J.C., He, Y., Bakkour, S., Patriub, V., Karnell, F.G., Xu, L., Allman, D., and Pear, W.S., Deltex-1 promotes B cell development at the expense of T cell development by antagonizing Notch-1, Immunity, 16, 231-243, 2002.
Izon, D.J., Punt, J.A., and Pear, W.S., Deciphering the role of Notch signaling in lymphopoiesis., Curr. Opin. Immunol., 14, 192-199, 2002.
Allman, D., Punt, J.A., Izon, D.J., Aster, J.C., and Pear, W.S. An invitation to T and more: Notch signaling in lymphoid development, Cell 109, S1-S11, 2002.
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