Christopher Vakoc, MD/PhD, is an assistant professor at Cold Spring Harbor Laboratory. His research focuses on mechanisms of chromatin regulation as it relates to the pathogenesis of cancer. His laboratory uses MLL-fusion acute myeloid leukemia as a model to study the role of chromatin regulators in this disease. Through a genetic screen, his lab identified the BET bromodomain protein BRD4 as a therapeutic target in leukemia.
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 aberrant signaling through chromatin. Such aberrant chromatin states are potentially reversible through use of organic small-molecule inhibitors; a concept that is driving a major pursuit in oncology to target chromatin regulators as a therapeutic approach.
Research in our laboratory investigates how chromatin regulators are integrated within the oncogenic signal transduction cascades that drive cancer cell growth. Our principal focus is on acute myeloid and lymphoid leukemias, with in an expanding interest in epithelial tumors. To this end, we employ genetically-engineered mouse models of cancer that recapitulate the cardinal features of the human disease, particularly with respect to therapeutic response. We have had a long-standing interest in the MLL proto-oncogene and its leukemogenic MLL-fusion protein derivatives. MLL is both a ‘writer’ and a ‘reader’ of histone H3 lysine 4 (H3K4) methylation: its SET domain catalyzes H3K4 methylation and its third PHD domain binds to H3K4 methylation. In leukemia, MLL is mutated via chromosomal translocation to form fusion proteins with corrupted chromatin regulatory functions. We previously identified how MLL uses its unique chromatin-binding activity to perpetuate active chromatin states through mitosis, a function called mitotic bookmarking. We continue to investigate molecular mechanisms employed by MLL and MLL-fusion proteins to regulate transcription in normal and transformed cell contexts.
Through a genetic screen, we recently identified the BET bromodomain protein BRD4 as a critical vulnerability 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 in leukemia. Remarkably, our work coincided with the development of potent small-molecule inhibitors of BET bromodomains. Using these agents, we pharmacologically validated BRD4-inhibition as a therapeutic strategy in a host of preclinical animal models of leukemia, findings that are now being translated into clinical development. Our lab continues to investigate the BRD4 pathway as a major chromatin-based signaling cascade that sustains c-MYC in hematopoietic malignancies. In addition, our genetic screening approach has revealed a plethora of chromatin-regulator vulnerabilities in many cancer types, fueling our continued efforts to understand and exploit these factors as candidate drug-targets in human disease.
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