RRC ID 57655
Author Asada S, Goyama S, Inoue D, Shikata S, Takeda R, Fukushima T, Yonezawa T, Fujino T, Hayashi Y, Kawabata KC, Fukuyama T, Tanaka Y, Yokoyama A, Yamazaki S, Kozuka-Hata H, Oyama M, Kojima S, Kawazu M, Mano H, Kitamura T.
Title Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.
Journal Nat Commun
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.
Volume 9(1)
Pages 2733
Published 2018-7-16
DOI 10.1038/s41467-018-05085-9
PII 10.1038/s41467-018-05085-9
PMID 30013160
PMC PMC6048047
MeSH Animals Bone Marrow / metabolism Bone Marrow / pathology Bone Marrow Transplantation CRISPR-Cas Systems Carcinogenesis / genetics* Carcinogenesis / metabolism Carcinogenesis / pathology Core Binding Factor Alpha 2 Subunit / genetics Core Binding Factor Alpha 2 Subunit / metabolism Female Gene Editing Gene Expression Regulation, Leukemic* HEK293 Cells HeLa Cells Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Humans Interferon Regulatory Factors / genetics Interferon Regulatory Factors / metabolism Leukemia, Myeloid / genetics* Leukemia, Myeloid / metabolism Leukemia, Myeloid / mortality Leukemia, Myeloid / pathology Male Mice Mice, Inbred C57BL Mutation RUNX1 Translocation Partner 1 Protein / genetics RUNX1 Translocation Partner 1 Protein / metabolism Repressor Proteins / genetics* Repressor Proteins / metabolism Signal Transduction Survival Analysis Tumor Suppressor Proteins / genetics* Tumor Suppressor Proteins / metabolism Ubiquitin Thiolesterase / genetics* Ubiquitin Thiolesterase / metabolism Ubiquitination Whole-Body Irradiation
IF 11.878
Times Cited 24
Resource
Cord blood stem cells for research