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. We have
developed an evolutionary based model for cancer development, Adaptive Oncogenesis. We are
currently exploring how reduced progenitor cellular fitness resulting from carcinogen exposure,
irradiation, 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 and non-small lung cancers. 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 cancer 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 malignancies.
Representative Publications:
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.
Porter, C.P. and J. DeGregori (2008). Interfering RNA-mediated purine analog
resistance for in vitro and in vivo cell selection. Blood 112, 4466-4474.
Marusyk A., M. Casás-Selves, C. J. Henry, V. Zaberezhnyy, J. Klawitter, U. Christians
and J. DeGregori (2009). Irradiation alters selection for oncogenic mutations in
hematopoietic progenitors. Cancer Research (in press).
Back to Top
|
