MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

Yosuke Komata, Akinori Kanai, Takahiro Maeda, Toshiya Inaba and Akihiko Yokoyama ()
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Yosuke Komata: National Cancer Center
Akinori Kanai: the University of Tokyo
Takahiro Maeda: Kyushu University Graduate School of Medical Sciences
Toshiya Inaba: Hiroshima University
Akihiko Yokoyama: National Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.

Date: 2023
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DOI: 10.1038/s41467-023-37712-5

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