Assessment of DCAF15 role in Acute Myeloid Leukemia

Project Summary Acute Myeloid Leukemia (AML) represents a highly aggressive hematologic malignancy characterized by a multitude of genetic alterations and an exceptionally poor prognosis. Genomic analyses of AML patients have unveiled recurrent mutations in the cohesin complex, with a prevalence ranging from 5.9% to 13.0%. The clinical success of proteasome inhibitors such as bortezomib, along with E3 ubiquitin ligase modulators, in the treatment of hematologic disorders underscores the significance of the Ubiquitin pathway as a promising target for cancer therapeutics. Consequently, understanding the functional roles of novel E3 ligases and their implications in normal and pathological hematopoiesis holds the potential for innovative therapeutic interventions. Our investigations have revealed a pivotal post-translational mechanism regulating genome architecture in AML through ubiquitin-dependent degradation of cohesin complex components. Specifically, we have identified DCAF15 as the E3 ligase responsible for orchestrating the degradation of cohesin- associated accessory proteins PDS5A and CDCA5. These degradation events play a critical role in modulating cohesin acetylation on chromatin, 3D genome organization, and DNA replication. Consequently, our preliminary data elucidates the cell-autonomous role of DCAF15 as a master regulator of cell proliferation by controlling cohesin dynamics. The primary objectives of this proposal are to establish a conceptual framework for understanding the significance of cohesin complex degradation in the context of AML in vivo and to evaluate potential therapeutic interventions. Specifically, we aim to (a) decipher the biological function of DCAF15 in myeloid development and leukemia in vivo, (b) investigate the role of cohesin acetylation in AML pathogenesis, and (c) develop small molecule degraders targeting DCAF15. The outcomes of this grant proposal promise to uncover intrinsic AML mechanisms and explore novel therapeutic avenues by harnessing the Ubiquitin pathway.