Research Program:

My lab primarily works with mouse models, and we frequently use gene knock-out mice and retroviral models of leukemogenesis. 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 (such as 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. We are exploring how reduced progenitor cellular fitness resulting from carcinogen exposure, inadequate diet or aging can select for adaptive oncogenic events and thereby promote the expansion and fixation of oncogenically initiated cells. While current views of carcinogenesis focus on oncogenic mutations as the limiting step, our studies support a novel rationale for links between tumorigenesis and carcinogenic contexts: these contexts may promote the clonal expansion of cells bearing particular initiating events, in part by reducing progenitor pool fitness which selects for adaptive oncogenic mutations.
Other studies in the lab are geared towards the development of novel therapeutic strategies to treat leukemias.
We perform genome-wide loss-of-function screens using RNA interference (RNAi) to identify genes whose inhibition will synergize with current targeted therapeutics to eliminate leukemic cells.  Our screens have identified a number of genes that synergistically inhibit chronic myelogenous leukemia cells in combination with the drug imatinib mesylate, and these genes have been validated as therapeutic targets by using both pharmacological and genetic approaches. These studies could lead to discovery of adjuvants to current therapies that will more effectively treat or possibly even cure common blood malignancies. Finally, other studies in the lab are testing whether yeast-based immunotherapies targeting drug resistance mutations can effectively prevent the development of drug resistant leukemias.

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:

• 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.
  

• 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.
  Marusyk, A, L. Wheeler, C. Mathews and J. DeGregori (2007). p53 mediates senescence-like arrest induced by chronic replicational stress. Mol. Cell. Biol. 27, 5336-5351.  PMID: 17515610 Marusyk, A. and J. DeGregori (2007). Declining cellular fitness with age promotes cancer initiation by selecting for adaptive oncogenic mutations (theory paper). BBA Reviews on Cancer 1785: 1-11.
  

• Tessem, J.S., J.N. Jensen, H. Pelli, X-M. Dai, X-H.
  

• Zong, E.R. Stanley, J. Jensen, and J. DeGregori (2008).
  Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration. Diabetes, 57:1605-17.

• Porter, C.P. and J. DeGregori (2008).  Interfering RNA-mediated purine analog resistance for in vitro and in vivo cell selection. Blood, in press.

• 1997-1999:V Foundation Scholar.
  

• 2000-2005:Leukemia and Lymphoma Society Scholar.
  

• 2006:Dean’s Mentoring Award
  

View of Recent Publications in PubMed