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The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency
Sheridan, Mathew Maqbool, Muhammad A Largeot, Anne Clayfield, Liam Xu, Jingru Moncaut, Natalia Sellers, Robert Whittle, Jessica Paggetti, J. Iqbal, M.
Sheridan, Mathew
Maqbool, Muhammad A
Largeot, Anne
Clayfield, Liam
Xu, Jingru
Moncaut, Natalia
Sellers, Robert
Whittle, Jessica
Paggetti, J.
Iqbal, M.
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Abstract
BACKGROUND: The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors' self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. METHODS: We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A
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Date
2024
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Article
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Sheridan M, Maqbool MA, Largeot A, Clayfield L, Xu J, Moncaut N, et al. The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency. J Hematol Oncol. 2024 Oct 8;17(1):91. PubMed PMID: 39380002. Pubmed Central PMCID: PMC11462755. Epub 2024/10/09. eng.