Research Program:

My lab primarily works with mouse models, and we frequently use gene knock-out mice. Studies to better understand the conditions that foster the initiation of leukemias and lymphomas are currently a major thrust of the lab. In particular, we are investigating how conditions of stress (particularly those that impair DNA replication) promote the competitive expansion of cells expressing particular oncogenes, and the mechanism whereby these oncogenes can improve cell cycle progression and survival under conditions of stress. In addition, our studies of E2F transcription factors range from the organismal level, such as the development of disease in E2F knock-out mice, to the molecular level, such as our mechanistic studies of E2F control of transcription.

Some current projects in the DeGregori lab:

Poor cell cycling in progenitor pools predisposes to tumor development. Contexts of impaired DNA replication , including those resulting from certain vitamin deficiencies and chemotherapeutics, can be paradoxically associated with increased tumor development. Using retroviral transduction of bone marrow stem cells followed by transplantation into mice, we have demonstrated that genetic and pharmacologic impairment of DNA replication promotes the development of leukemias caused by Bcr-Abl as a result of poor competition among hematopoietic stem and progenitor cells. In contrast, competent replication among hematopoietic progenitors is inherently tumor suppressive, preventing the expansion of Bcr-Abl expressing progenitors. We are currently determining the signaling pathways controlled by Bcr-Abl that contribute to this oncogene's ability to overcome genetic and chemotherapeutic contexts of replicative stress. In addition, we are developing a model of treatment related acute myelogenous leukemia to ask whether these leukemias in part result from chemotherapy mediated inhibition of the competitive capacity of normal progenitors relative to oncogene expressing progenitors. Further understanding of the role of competitive interactions among blood progenitor cells in leukemogenesis and influences of chemotherapeutic treatments should help develop strategies to prevent and treat leukemias.

The development of insulin dependent diabetes in E2F1/E2F2 mutant mice reveals important roles for bone marrow (BM) derived cells in preventing exocrine pancreatic degeneration induced b islet destruction. Finally, we have discovered that mice mutant for E2F1 and E2F2 develop non-autoimmune insulin dependent diabetes with high penetrance, and we have shown that diabetes in part results from hematopoietic deficiencies in these mice. We are currently trying to understand roles for hematopoietic cells in the maintenance of bislet cells in the face of stress. These studies indicate a normal role for hematopoietic cells in supporting the survival and maintenance of b islet cells, and may indicate therapeutic approaches to augment these blood cell types in diabetic patients.

Key Publications:

• Zhu, J.W., S. J. Field, L. Gore, M. Thompson, H. Yang, Y. Fujiwara, R. D. Cardiff, M. Greenberg, S. H. Orkin, and J. DeGregori. (2001). E2F1 and E2F2 Determine Thresholds for Antigen-Induced T-Cell Proliferation and Suppress Tumorigenesis. Mol. Cell. Biol. 21 8547-8564.
• DeGregori, J. (2002). The genetics of the E2F transcription factor family: shared roles and unique functions. Biochemica et Biophysica Acta 1602, 131-150.
• Wan, Y.Y. and J. DeGregori (2003). The survival of antigen stimulated T cells requires NF?B mediated inhibition of p73 expression. Immunity 18, 331-342.
• Li, F.X., J.Z. Zhu, C. Hogan and J. DeGregori (2003). Defective gene expression , S phase progression and maturation during hematopoiesis in E2F1/E2F2 mutant mice. Mol. Cell. Biol., 23, 3607-3622.
• Li, F.X., J.W. Zhu, J. Tessem, J. Beilke, M. Varella-Garcia, J. Jensen, C. J. Hogan and J. DeGregori (2003). The development of diabetes in E2f1/E2f2 mutant mice reveals important roles for bone marrow derived cells in preventing islet cell loss. Proc. Natl. Acad. Sci. USA 100, 12935-12940.
• DeRyckere, D. and J. DeGregori (2005). E2F1 and E2F2 are differentially required for homeostasis-driven and antigen-induced T cell proliferation in vivo. J Immunology, 175:647-55.
• Bilousova G., A. Marusyk, C. Porter, R. Cardiff and J. DeGregori (2005). Impaired DNA replication in progenitor cell pools promotes leukemogenesis. PLoS Biology, 3(12):e401 [ePub ahead of print].
  

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