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Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies.


ABSTRACT: Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588X Tg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588X Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588X Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.

SUBMITTER: Yang H 

PROVIDER: S-EPMC5774208 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Additional Sex Combs-Like 1 (<i>ASXL1</i>) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a <i>Vav1</i> promoter-driven <i>Flag-Asxl1</i><sup><i>Y588X</i></sup> transgenic mouse model, <i>Asxl1</i><sup><i>Y588X</i></sup> Tg, to express a truncated FLAG-ASXL1<sup>aa1-587</sup> protein in the hematopoietic system. The <i>Asxl1</i><sup><i>Y588X</i></sup> Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival,  ...[more]

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