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Blood. 2017 Nov 7. pii: blood-2017-06-789669. doi: 10.1182/blood-2017-06-789669. [Epub ahead of print]

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

Author information

  • 1Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, United States.
  • 2Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, United States.
  • 3Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, United States.
  • 4Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, United States.
  • 5Department of Neurological Surgery, The Miami Project to Cure Paralysis, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, United States.
  • 6Department of Internal Medicine, University of Miami Miller School of Medicine, United States.
  • 7State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  • 8Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  • 9Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, United States; fxy37@med.miami.edu.

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-Seq analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared to wildtype cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hyper-sensitivity 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.

PMID:
29113963
DOI:
10.1182/blood-2017-06-789669
[PubMed - as supplied by publisher]
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