Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Nature Communications
Shuhei AsadaT Kitamura

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.

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Citations

Mar 31, 2019·Cellular and Molecular Life Sciences : CMLS·Shuhei AsadaToshio Kitamura
Dec 6, 2019·British Journal of Haematology·Luke JonesJonathan Bond
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Datasets Mentioned

BETA
GSE114861

Methods Mentioned

BETA
immunoprecipitation
monobubiquitination
FACS
transfection
ubiquitination
immunoprecipitation assay
deubiquitination
RNA-Seq
chip

Software Mentioned

TopHat2
DESeq2
Mascot
Flowjo
LabWorks
GSEA

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