Assistant Professor
M.D., Ph.D. University of Pennsylvania, 2007

Chromatin; epigenetics; acute myeloid leukemia; self-renewal; RNAi screening; mouse models of cancer

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Cancer cells are characterized by altered chromatin landscapes and commonly exploit epigenetic regulators to maintain oncogenic transcriptional programs. This is particularly evident in acute myeloid leukemia – an aggressive hematopoietic cancer that frequently harbors aberrant chromatin. Epigenetic changes in leukemia are often a consequence of direct somatic mutation of genes encoding chromatin regulators, which can function as oncogenes or tumor-suppressors in this disease. Since oncogenic alterations of chromatin are potentially reversible and amendable to drug intervention, targeting epigenetic pathways holds promise as a therapeutic strategy in leukemia as well as other cancers.

Our research investigates how chromatin regulatory pathways participate in the pathogenesis of cancer. To this end, we employ genetically engineered mouse leukemia models to specifically interrogate the epigenetic requirements for disease maintenance in vivo. Of particular interest are leukemias carrying rearrangements of the MLL gene, which encodes a histone H3K4 methyltransferase involved in normal and malignant hematopoiesis. MLL-rearranged leukemias are associated with chemotherapy resistance and often harbor characteristic abnormalities of chromatin. A major focus of our work is to expose novel epigenetic vulnerabilities in MLL-leukemia for direct exploitation using small-molecules as novel anti-leukemia agents. An additional interest in our laboratory is to elucidate mechanisms of epigenetic inheritance employed by MLL and other chromatin regulators to understand how transcriptional states are faithfully transmitted through cell division. To investigate the biological mechanisms of chromatin regulation, we employ a host of biochemical and cell-biological techniques applied to cells obtained from primary tissue, as well as from tissue culture systems.

Selected Publications

Steger, D.J., Lefterova, M.I., Stonestrom, A.J., Schupp, M., Zhuo, D., Kim, J., Chen, J., Lazar, M.A., Blobel, G.A. and Vakoc, C.R. 2008. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Molecular and Cellular Biology 28: 2825–39.

Vakoc, C.R., Wen, Y.W., Johnstone, C.N., Rustgi, A.K., Gibbs, R.A. and Blobel, G.A. 2009. Low frequency of MLL3 mutations in colorectal carcinoma. Cancer Genetics and Cytogenetics 189: 140–1.

Chou, S.T., Khandros, E., Bailey, L.C., Nichols, K.E., Vakoc, C.R., Yao, Y., Huang, Z., Crispino, J.D., Hardison, R.C., Blobel, G.A. and Weiss, M.J. 2009. Graded Repression of PU.1/Sfpi1 gene transcription by GATA factors regulates hematopoietic cell fate. Blood 114(5): 983–94.

Blobel, G.A., Kadauke, S., Wang, E., Lau, A.W., Zuber, J., Chou, M.M. and Vakoc, C.R. 2009. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Molecular Cell 36: 970–983.

Speck, N.A. and Vakoc, C.R. 2010. PAF is in the cabal of MLL1-interacting proteins that promote leukemia. Cancer Cell 17: 531–2.