Arthur, B. | Search bioRxiv

bioRxiv2024

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

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.

cancer biology↗

bioRxiv2017

Reported Drosophila Courtship Song Rhythms Remain Data Analysis Artifacts

From 1980 to 1992, a series of influential papers reported on the discovery, genetics, and evolution of a periodic cycling of the interval between Drosophila male courtship song pulses. The molecular mechanisms underlying this periodicity were never described. To reinitiate investigation of this phenomenon, we performed automated segmentation of songs, but failed to detect the proposed periodicity [Arthur BJ et al. (2013) BMC Biol 11:11; Stern DL (2014) BMC Biol 12:38]. Kyriacou CP et al. [(2017) PNAS 114:1970-1975] report that we failed to detect song rhythms because i) our flies did not sing enough and ii) our segmenter did not identify many of the song pulses. Kyriacou et al. manually annotated a subset of our recordings and reported that two strains displayed rhythms with genotype-specific periodicity, in agreement with their original reports. We cannot replicate this finding and show that the manually-annotated data, the original automatically segmented data, and a new data set provide no evidence for either the existence of song rhythms or song periodicity differences between genotypes. Furthermore, we have re-examined our methods and analysis and find that our automated segmentation method was not biased to prevent detection of putative song periodicity. We conclude that there is currently no evidence for the existence of Drosophila courtship song rhythms.\n\nSignificance statementPrevious studies have reported that male vinegar flies sing courtship songs with a periodic rhythm of approximately 55 seconds. Several years ago, we showed that we could not replicate this observation. Recently, the original authors have claimed that we failed to find rhythms because 1) our flies did not sing enough and 2) our software for detecting song did not detect all song events. They claimed that they could detect rhythms in song annotated by hand. We report here that we cannot replicate their observation of rhythms in the hand-annotated data or in any dataset and that our original methods were not biased against detecting rhythms. We conclude that song rhythms cannot be detected.

animal behavior and cognition↗