Functionally dissecting MECOM gene regulation in high-risk leukemia

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease that continues to have a poor prognosis with less than one-third of patients achieving a cure from their disease. While the identification of genomic subtypes has enabled some risk stratification, it is increasingly evident that variation in cell states in AML and particularly the

presence of leukemia progenitors that co-opt hematopoietic stem cell (HSC) programs appear to confer a particularly poor prognosis. Despite these robust descriptive observations, however, the molecular drivers of these high-risk gene expression programs that alter cell state have remained largely undefined. Our research

group recently characterized a gene network that is regulated by the HSC master transcription factor MECOM and co-opted in high-risk forms of AML. However, we still lack an understanding of the mechanisms by which MECOM regulates this network and how it can be therapeutically hijacked to improve treatment of leukemias.

To better interrogate MECOM’s direct function in AML, we engineered an AML cell-line model in which MECOM can be rapidly and controllably degraded by addition of a small molecule. Assessments of changes in transcription and chromatin accessibility immediately following complete MECOM degradation implicate

MECOM as an epigenetic repressor of a pro-myeloid differentiation program. Importantly, the majority of these differentially accessible chromatin regions are also directly bound by MECOM in the absence of degradation, suggesting that these observed changes are a direct consequence of MECOM ablation. The observed repressive

function of MECOM is also consistent with its reported interactions with the CtBP family of co-repressive factors. However, there are fundamental knowledge gaps both in the identity of MECOM’s direct targets across primary AMLs and the mechanisms underlying its repressive function, both of which could be therapeutically useful. This

study consists of two aims to investigate: (1) the identity of genetic targets directly regulated by MECOM function in high-risk AMLs, and (2) the epigenetic mechanisms by which MECOM represses differentiation programs to maintain AML progenitor cells. For this F31 award, the PI has designed a research strategy and training program

that will provide him with: (1) fundamental expertise in genomics, bioinformatics, and cancer biology, (2) an expert group of mentors and collaborators to promote not only research expertise, but also career-long academic skills including grantsmanship and scientific communication, and (3) experience performing rigorous,

mechanistic and foundational biomedical research in preparation for his career goal as an academic scientist. This proposal will take place in the rich and collaborative Harvard Medical School and Boston Children’s Hospital research environments. Completion of this work is expected to identify the direct transcriptional targets of

MECOM in high-risk AML and elucidate the epigenetic mechanisms by which MECOM drives leukemogenesis. These results will have profound implications for the rationale pursuit of high-confidence, tractable targets that can be therapeutically manipulated for the treatment of myeloid malignancies currently with dismal outcomes.