KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.
- Abstract:
- UNLABELLED: NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia. SIGNIFICANCE: KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.
- Authors:
- NL Michmerhuizen, EB Heikamp, I Iacobucci, M Umeda, B Arthur, V Mishra, CS Park, D Di Giacomo, R Hiltenbrand, Q Gao, S Radko-Juettner, J Lott, C Martucci, V Subramanyam, C Hatton, DV Wenge, P Baviskar, P Portola, A Claquin, B Chandra, DW Baggett, A Khalighifar, H Huang, P Zhou, L Long, H Shi, Y Sun, EK Papachristou, C Sekhar Reddy Chilamakuri, FN de Luna Vitorino, JM Gongora, H Wu, SB Pounds, LJ Janke, A Kentsis, CS D'Santos, BA Garcia, RW Kriwacki, H Chi, JM Klco, SA Armstrong, CG Mullighan
- Journal:
- Cancer Discov
- Citation info:
- 15(10):2096-2116
- Publication date:
- 6th Oct 2025
- Full text
- DOI