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Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Alex Kentsis

Alex Kentsis


Memorial Sloan Kettering Cancer Center

Project Term: July 1, 2019 - June 30, 2024

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Lay Abstract

This project will explore therapeutic options for targeting the gene transcription regulator MYB with the goal of treating AML without damaging healthy cells. Despite intense efforts, the cure rates of pediatric and adult patients with acute myeloid leukemia are inadequate. Resistance to chemotherapy is prevalent, demonstrating the need to better understand the molecular basis of cancer and how to target consequent molecular abnormalities. Despite considerable advances in our understanding of the oncogenic mutations that drive cancer development, conventional chemotherapy remains the dominant approach to achieve cure, but it is inadequate for most patients. Aberrant control of gene expression is increasingly recognized as a fundamental feature and cause of human cancers. Genes are regulated by a complex process involving transcription factors, which turn gene transcription on or off, and epigenetic factors, which reversibly modify the DNA and surrounding proteins that function to interpret signals that guide the transcription factors. However, the precise mechanisms by which gene regulation occurs in cancers such as acute myeloid leukemia (AML), remain elusive. For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes of AML, but the molecular pathophysiology and therapeutic accessibility of these mutations remain poorly defined. My research focuses on the elucidation of the molecular mechanisms of leukemic gene expression by the transcription factor MYB, which is absolutely required for most AMLs. My project aims to define the complex of proteins that interacts with MYB to control gene expression – known as the “enhanceosome” – and compare its assembly and composition in AML cells to its assembly and composition in normal cells. We have identified several inhibitors of the MYB pathway, and we will determine how these also affect the enhanceosome. We have also shown that suppression of MYB activity kills AML cells but has no effect on healthy blood cells. Therefore, we are actively developing therapeutic strategies to suppress leukemic MYB activity in mouse and human leukemia models by directly inhibiting MYB as well as combining MYB inhibition with inhibition of other partners in the MYB enhanceosome, which may provide therapeutic synergy. This research is expected to lead immediately to clinical trials of improved therapies for patients, including children with therapy-refractory AML. This project should have a broad and lasting impact given that MYB is aberrantly activated in virtually all known blood cancers.

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