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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Bone Marrow Transplantation
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CRISPR-Cas Systems
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism
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Female
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Gene Editing
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Gene Expression Regulation, Leukemic*
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HEK293 Cells
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HeLa Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism
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Leukemia, Myeloid / genetics*
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Leukemia, Myeloid / metabolism
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Leukemia, Myeloid / mortality
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Leukemia, Myeloid / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mutation
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RUNX1 Translocation Partner 1 Protein / genetics
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RUNX1 Translocation Partner 1 Protein / metabolism
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Signal Transduction
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Survival Analysis
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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Ubiquitin Thiolesterase / genetics*
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Ubiquitin Thiolesterase / metabolism
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Ubiquitination
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Whole-Body Irradiation
Substances
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ASXL1 protein, human
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BAP1 protein, human
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Core Binding Factor Alpha 2 Subunit
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Homeodomain Proteins
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Interferon Regulatory Factors
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RUNX1 Translocation Partner 1 Protein
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RUNX1 protein, human
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RUNX1T1 protein, human
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Repressor Proteins
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Tumor Suppressor Proteins
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interferon regulatory factor-8
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HoxA protein
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Ubiquitin Thiolesterase