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.
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.