Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Shuhei Asada, Susumu Goyama, Daichi Inoue, Shiori Shikata, Reina Takeda, Tsuyoshi Fukushima, Taishi Yonezawa, Takeshi Fujino, Yasutaka Hayashi, Kimihito Cojin Kawabata, Tomofusa Fukuyama, Yosuke Tanaka, Akihiko Yokoyama, Satoshi Yamazaki, Hiroko Kozuka-Hata, Masaaki Oyama, Shinya Kojima, Masahito Kawazu, Hiroyuki Mano and Toshio Kitamura ()
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Shuhei Asada: The University of Tokyo
Susumu Goyama: The University of Tokyo
Daichi Inoue: The University of Tokyo
Shiori Shikata: The University of Tokyo
Reina Takeda: The University of Tokyo
Tsuyoshi Fukushima: The University of Tokyo
Taishi Yonezawa: The University of Tokyo
Takeshi Fujino: The University of Tokyo
Yasutaka Hayashi: The University of Tokyo
Kimihito Cojin Kawabata: The University of Tokyo
Tomofusa Fukuyama: The University of Tokyo
Yosuke Tanaka: The University of Tokyo
Akihiko Yokoyama: National Cancer Center Tsuruoka Metabolomics Laboratory
Satoshi Yamazaki: The University of Tokyo
Hiroko Kozuka-Hata: The University of Tokyo
Masaaki Oyama: The University of Tokyo
Shinya Kojima: The University of Tokyo
Masahito Kawazu: The University of Tokyo
Hiroyuki Mano: The University of Tokyo
Toshio Kitamura: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

Date: 2018
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DOI: 10.1038/s41467-018-05085-9

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