MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

Mullighan, C. G.; Michmerhuizen, N. L.; Heikamp, E. B.; Iacobucci, I.; Umeda, M.; Arthur, B.; Mishra, V.; Di Giacomo, D.; Hiltenbrand, R.; Gao, Q.; Radko-Juettner, S.; Lott, J.; Martucci, C.; Subramanyam, V.; Hatton, C.; Baviskar, P.; Portola, P.; Claquin, A.; Chandra, B.; Baggett, D. W.; Khalighifar, A.; Huang, H.; Zhou, P.; Long, L.; Shi, H.; Sun, Y.; Papachristou, E. K.; Chilamakuri, C. S. R.; Vitorino, F. N. d. L.; Gongora, J. M.; Janke, L.; Kentsis, A.; D'Santos, C. S.; Garcia, B. A.; Kriwacki, R. W.; Chi, H.; Klco, J. M.; Armstrong, S. A.

doi:10.1101/2024.12.02.624182

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bioRxiv · 10.1101/2024.12.02.624182

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

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Abstract

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 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 Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 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. SIGNIFICANCE STATEMENTMOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy in NUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.

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Mullighan, C. G., Michmerhuizen, N. L., Heikamp, E. B., Iacobucci, I., Umeda, M., Arthur, B., Mishra, V., Di Giacomo, D., Hiltenbrand, R., Gao, Q., Radko-Juettner, S., Lott, J., Martucci, C., Subramanyam, V., Hatton, C., Baviskar, P., Portola, P., Claquin, A., Chandra, B., Baggett, D. W., Khalighifar, A., Huang, H., Zhou, P., Long, L., Shi, H., Sun, Y., Papachristou, E. K., Chilamakuri, C. S. R., Vitorino, F. N. d. L., Gongora, J. M., Janke, L., Kentsis, A., D'Santos, C. S., Garcia, B. A., Kriwacki, R. W., Chi, H., Klco, J. M., Armstrong, S. A.. 2024-12-05. MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia. https://doi.org/10.1101/2024.12.02.624182

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