M.D., Ph.D. University of Pennsylvania, 2007
Chromatin; transcriptional regulation; acute myeloid leukemia; BET bromodomains; lysine methyltransferases
Cancer cells exploit the chromatin regulatory machinery to maintain oncogenic transcriptional programs. This is particularly evident in leukemia – a hematopoietic cancer where genes encoding chromatin regulators often function as driver oncogenes and/or tumor-suppressors. Hence, many forms of leukemia can be considered a direct consequence of deregulated chromatin signaling.
In our laboratory we investigate how chromatin regulatory proteins participate in the pathogenesis of cancer. To this end, we employ genetically-engineered mouse models of leukemia that recapitulate the key pathological features of the human disease. We recently identified the BET bromodomain protein BRD4 as a critical vulnerability and drug target in acute myeloid leukemia. BRD4 is a chromatin reader protein that utilizes its tandem bromodomains to recognize acetylated forms of histone H3 and H4. We found that BRD4 functions as a critical upstream regulator of c-MYC expression, thereby sustaining aberrant self-renewal of leukemia cells. Our work coincided with the development of potent small-molecule inhibitors of BET bromodomains and, using these agents, we pharmacologically validated BRD4-inhibition as a therapeutic strategy in animal models of leukemia; findings that are now being translated into clinical development. Our lab continues to investigate the mechanism of BRD4 function in leukemia and have identified several cis- and trans-acting components acting in the same chromatin-based signaling pathway. In addition, our genetic screening approach has revealed a multitude of epigenetic vulnerabilities in many cancer types, fueling our continued efforts to understand and exploit these factors as candidate drug-targets in oncology.
Please visit Chris' Lab home page.
Shi, J., Wang, E., Zuber, J., Rappaport, A., Taylor, M., Johns, C., Lowe, S.W., and Vakoc, C.R. 2013. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9; NrasG12D acute myeloid leukemia. Oncogene 32: 930–938.
Wang, E., Kawaoka, S., Yu, M., Shi, J., Ni, T., Yang, W., Shu, J., Roeder, R.G., and Vakoc, C.R. 2013. Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Proc. Natl. Acad. Sci. USA 110: 3901–3906.
Zuber, J., Shi, J., Wang, E., Rappaport, A.R., Herrmann, H., Sison, E.A., Magoon, D., Qi, J., Blatt K, Wunderlich, M., Taylor, M.J., Johns,C., Chicas, A., Mulloy, J.C., Kogan, S.C., Brown, P., Valent, P., Bradner, J.E., Lowe S.W., and Vakoc, C.R. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia. Nature 478: 524–528.
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. Mol. Cell 36: 970–983.
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. Mol. Cell. Biol. 28: 2825–2839.