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Blood. 2018 Jan 18;131(3):328-341. doi: 10.1182/blood-2017-06-789669. Epub 2017 Nov 7.

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

Yang H1,2, Kurtenbach S1,3, Guo Y1,2, Lohse I1,4, Durante MA1,3, Li J1,2, Li Z1,2, Al-Ali H1,5, Li L1,6, Chen Z7, Field MG1,3, Zhang P1,2, Chen S1,2, Yamamoto S1,2, Li Z1,2, Zhou Y7, Nimer SD1,2,6, Harbour JW1,2,3, Wahlestedt C1,4, Xu M1,2, Yang FC1,2.

Author information

  • 1Sylvester Comprehensive Cancer Center.
  • 2Department of Biochemistry and Molecular Biology.
  • 3Bascom Palmer Eye Institute.
  • 4Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences.
  • 5Department of Neurological Surgery, The Miami Project to Cure Paralysis, Peggy and Harold Katz Family Drug Discovery Center, and.
  • 6Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL; and.
  • 7State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.


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.

[Available on 2019-01-18]
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