期刊
BLOOD
卷 131, 期 3, 页码 328-341出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-06-789669
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资金
- National Institutes of Health, National Cancer Institute [CA172408, CA185751]
- National Heart, Lung, and Blood Institute [HL112294]
- Chinese Academy of Medical Sciences [202016-I2M-2-001]
- Alcon Research Institute
- Sylvester Comprehensive Cancer Center [PG006470]
- University of Miami Sheila and David Fuente Graduate Program in Cancer Biology
- Center for Computational Science Fellowship
- National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [AA023781]
- National Institute on Drug Abuse [DA042650]
- National Institutes of Health National Eye Institute [P30EY014801]
- Department of Defense (329 Grant) [W81XWH-13-1-0048]
- Research to Prevent Blindness
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-Asxl1(Y588X) transgenic mouse model, Asxl1(Y588X)Tg, to express a truncated FLAGASXL1(aa1- 587) protein in the hematopoietic system. The Asxl1(Y588X)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 ASXL1(aa1-587) truncating protein expression results in more open chromatin in cKit1 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 ASXL1(aa1-587) acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1(Y588X)Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1(aa1-587) 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.
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