M.D., Ph.D. University of Pennsylvania, 2007
Cancer cells achieve their pathogenicity by changing which genes are on and off. To maintain these changes in gene expression, cancer cells rely on proteins that interact with and modify their chromatin. My group investigates how chromatin regulatory proteins contribute to the aggressiveness of acute myeloid leukemia, thereby identifying new therapeutic targets.
Acute myeloid leukemia (AML) is a particularly devastating and aggressive blood cancer that is currently incurable in 70% of patients. Research in Chris Vakoc’s lab seeks to understand this disease as well as others, such as lymphoid leukemias and epithelial tumors, by studying them at the level of genomic regulation. He is particularly interested in the proteins that regulate chromatin in the nucleus of the cell. To identify proteins involved in AML, which may also be targets for drug therapy, he deploys large-scale genetic screens using RNA interference (RNAi) as well as genetically engineered mouse models that display the hallmarks of human cancer. In collaboration with Jay Bradner at the Dana-Farber Cancer Institute, Vakoc has shown that the small-molecule drug candidate JQ1 has potent anti-AML activity. It works by suppressing the protein Brd4, which is a critical regulator of the potent oncogene c-Myc. JQ1 is currently in clinical trials as a therapeutic strategy for AML. Vakoc’s team identified other chromatin regulators, including PRC2 and RNF20, that if blocked with small-molecule inhibitors may halt AML. This year, Vakoc’s lab gained new insights into the mechanism behind these drug targets when he found that Brd4 and other proteins required for AML bind to enhancers, short stretches of DNA more than a million bases away from the oncogene c-Myc. When Brd4 binds to the enhancer, it bends the DNA within the nucleus so that it touches the c-Myc region of the genome and activates it, causing cells to proliferate without restraint. Understanding how these proteins function in AML will allow researchers to design more effective and safer therapies to treat this intractable cancer.
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.
Scientists discover how leukemia cells exploit ‘enhancer’ DNA elements to cause lethal disease
November 27, 2013
CSHL scientists identify a new strategy for interfering with a potent cancer-causing gene
February 14, 2013
‘Druggable’ protein complex identified as a therapeutic target in acute myeloid leukemia
Unconventional hunt for new cancer targets leads to a powerful drug candidate for leukemia
‘A’ award from Alex’s Lemonade Stand Foundation
"V Scholar" for 2012 by The V Foundation for Cancer Research