Phone: (303) 724-3230
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. Using mouse models, 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. In the last year, our studies have focused on how aging-associated inflammation can perturb hematopoiesis. In particular, we have shown that inflammation is sufficient to recapitulate effects on B-lymphopoiesis associated with aging, including altered signaling, gene expression and metabolic profiles. These changes lead to selection for oncogenic mutations that can correct these deficiencies, thus promoting leukemogenesis.
Other studies in the lab are geared towards the development of novel therapeutic strategies to treat leukemias and non-small cell lung cancers (NSCLC). 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 and acute myelogenous leukemia cells, as well as NSCLC cells, in combination with tyrosine kinase inhibitors, and these genes have been validated as therapeutic targets by using both pharmacological and genetic approaches. In particular, for myeloid leukemias we are now focused on key metabolic pathways (including the pentose phosphate pathway and mitochondrial integrity maintenance) that become critical for leukemia survival during kinase inhibition. These studies could lead to discovery of adjuvants to current therapies that will more effectively treat or possibly even cure common malignancies.
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 69, 7262-7269.
Gregory, M., T. Phang, P. Neviani, F. Alvarez-Calderon, V. Zaberezhnyy, R. Williams, T. O’Hare, C. Eide, B. Druker, D. Perrotti and J. DeGregori (2010). Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell, 18, 74-87.
Marusyk A, C. Porter, V. Zaberezhnyy and J. DeGregori (2010). Irradiation selects for p53 deficient hematopoietic progenitors. PLoS Biology, 8:e1000324.
Henry, C.J., A. Marusyk, B. Adane, V. Zaberezhnyy and J. DeGregori (2010). Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis. Proc. Natl. Acad. Sci. USA, 107: 21713-21718.
Porter, C.C., D. Baturin, R. Choudhary and J. DeGregori (2011). The relative fitness of hematopoietic progenitors influences leukemia progression. Leukemia, 25:891-5.
DeGregori, J. (2011). Evolved tumor suppression: why are we so good at not getting cancer? (Perspective) Cancer Research, 71: 3739-3744.
Porter, C.C., J. Kim, S. Fosmire, C. M. Gearheart, A. van Linden, D. Baturin, V. Zaberezhnyy, P. R. Patel, D. Gao, A. C. Tan, and J. DeGregori (2012). Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and novel therapeutic target in acute myeloid leukemia. Leukemia, 26:1266-76.
Casas-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC, Scarborough HA, Bunn PA, Jr., Chan DC, Tan AC, DeGregori J (2012). Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res, 72:4154-64.
Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, Tentler JJ, Eckhardt SG, Tan AC, DeGregori J, Espinosa JM. (2012) ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nature Chem Biol, 8:646-54.
DeGregori J. (2013) Challenging the axiom: Does the occurrence of oncogenic mutations truly limit cancer development with age? Oncogene, 32, 1869–1875.
Alvarez-Calderon, F., Gregory, M. A., and Degregori, J. (2013). Using functional genomics to overcome therapeutic resistance in hematological malignancies. Immunologic Research 55, 100-115.