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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 | Toshio Kitamura
Nature communications | 2018

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.

Pubmed ID: 30013160

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

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