Supplementary Figure S7 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

Michmerhuizen, Nicole L.; Heikamp, Emily B.; Iacobucci, Ilaria; Umeda, Masayuki; Arthur, Bright; Mishra, Vibhor; Park, Chun Shik; Di Giacomo, Danika; Hiltenbrand, Ryan; Gao, Qingsong; Radko-Juettner, Sandi; Lott, Josi; Martucci, Cynthia; Subramanyam, Varsha; Hatton, Charlie; Wenge, Daniela V.; Baviskar, Pradyuamna; Portola, Pablo; Claquin, Aurelie; Chandra, Bappaditya; Baggett, David W.; Khalighifar, Ali; Huang, Hongling; Zhou, Peipei; Long, Lingyun; Shi, Hao; Sun, Yu; Papachristou, Evangelia K.; Sekhar Reddy Chilamakuri, Chandra; de Luna Vitorino, Francisca N.; Gongora, Joanna M.; Wu, Huiyun; Pounds, Stanley B.; Janke, Laura J.; Kentsis, Alex; D’Santos, Clive S.; Garcia, Benjamin A.; Kriwacki, Richard W.; Chi, Hongbo; Klco, Jeffery M.; Armstrong, Scott A.; Mullighan, Charles G.

doi:10.1158/2159-8290.30284419

Supplementary Figure S7 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

https://doi.org/10.1158/2159-8290.30284419

journal contribution

posted on 2025-10-06, 07:20 authored by 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. Mullighan

Supplementary Figure S7 shows that KAT6A/7 and Menin inhibition alter gene expression and remodel chromatin in NUP98-rearranged cells.

Funding

Hyundai Hope On Wheels (Hope On Wheels)

American Society of Hematology (ASH)

Burroughs Wellcome Fund (BWF)

Charles H. Hood Foundation (CHF)

Cancer Moonshot (Misión contra el Cáncer)

Center for Cancer Research (CCR)

Leukemia and Lymphoma Society (LLS)

St. Jude Children’s Research Hospital

History

Related Materials

1.
DOI - Is supplement to KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

ARTICLE ABSTRACT

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. 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.

Supplementary Figure S7 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia