Different domains of KAT6A are required to maintain KAT6A/MOZ or KMT2A/MLL rearranged AMLs: implications for therapies. Mus musculus

Acute myeloid leukemia is a deadly disease, with a dismal 5-year survival rate of around 20%, highlighting an urgent need for more effective therapies. KAT6A (MOZ/MYST3) is a lysine acetyltransferase that interacts with the transcription factor/methyltransferase, KMT2A (MLL1), in normal early hematopoiesis. Both KAT6A and KMT2A are translocated in AMLs, and the products of these rearrangements are thought to disrupt critical pathways, co-regulated by these proteins. Consequently, targeting KAT6A may hold promise in mitigating the dysregulation of these pathways. We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119, in KAT6A rearranged AML. We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with decreased stemness and leukemia pathways at the transcriptome level and loss of binding of the fusion protein at critical regulators of these pathways. To investigate a broader therapeutic role of targeting KAT6A in AMLs, we employed, in addition to WM-1119, two novel genetic murine KAT6A models combined with the most common KMT2A rearranged AML, MLL-AF9 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. Our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a limited role in KMT2Ar leukemogenicity and suggest that targeting the entire KAT6A protein may represent a more effective therapeutic strategy. Therefore, while inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients, targeted degradation of KAT6A may represent a more appropriate therapeutic approach for KMT2Ar AMLs.