KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia
Nicole L. Michmerhuizen, Emily B. Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V. Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W. Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K. Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N. de Luna Vitorino, Joanna M. Gongora, Huiyun Wu, Stanley B. Pounds, Laura J. Janke, Alex Kentsis, Clive S. D'Santos, Benjamin A. Garcia, Richard W. Kriwacki, Hongbo Chi, Jeffery M. Klco, Scott A. Armstrong, Charles G. MullighanAbstract
NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). 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. Here 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 AML.