ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

Project Summary Despite intense efforts, the long-term cure rates of patients with acute myeloid leukemia are inadequate. Resistance to chemotherapy is prevalent, and targets for molecular therapies are only beginning to be defined. For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes of AML, but their molecular pathophysiology and pharmacologic accessibility remain poorly defined. We have now found that leukemogenic gene expression in AML requires distinct molecular interactions between the pioneer transcription factor MYB and its coactivator CBP. Remarkably, peptidomimetic inhibitors of MYB transcriptional coactivation exhibit potent anti-leukemia activity in most molecular subtypes of AML while sparing healthy cells. The central hypothesis of this proposal is that defining and blocking the molecular mechanisms of aberrant transcriptional coactivation in AML will lead directly to improved therapies for patients. Aim 1 will define the molecular mechanisms of aberrant activation of leukemic MYB transcription factor complexes that control oncogenic gene expression. Aim 2 will pursue the preliminary evidence that peptidomimetic and targeted small molecule inhibitors can be used to dismantle leukemic transcriptional complexes in vivo and develop effective therapeutic strategies using accurate genetic and patient-derived preclinical mouse models. Successful completion of this project is expected to yield essential molecular mechanisms and effective therapies of aberrant transcription factors and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This should have broad and lasting significance for understanding and treating refractory leukemias in particular and human cancer generally.