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

Hui Yang, Stefan Kurtenbach, Ying Guo, Ines Lohse, Michael A. Durante, Jianping Li, Zhaomin Li, Hassan Al-Ali, Lingxiao Li, Zizhen Chen, Matthew G. Field, Peng Zhang, Shi Chen, Shohei Yamamoto, Zhuo Li, Yuan Zhou, Stephen D Nimer, J. William Harbour, Claes R Wahlestedt, Mingjiang XuFeng-Chun Yang

Research output: Contribution to journalArticle

34 Scopus citations

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, Asxl1Y588XTg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588XTg 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 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 ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588XTg 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. (Blood. 2018;131(3):328-341)

Original languageEnglish (US)
Pages (from-to)328-341
Number of pages14
JournalBlood
Volume131
Issue number3
DOIs
StatePublished - Jan 18 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Yang, H., Kurtenbach, S., Guo, Y., Lohse, I., Durante, M. A., Li, J., Li, Z., Al-Ali, H., Li, L., Chen, Z., Field, M. G., Zhang, P., Chen, S., Yamamoto, S., Li, Z., Zhou, Y., Nimer, S. D., William Harbour, J., Wahlestedt, C. R., ... Yang, F-C. (2018). Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood, 131(3), 328-341. https://doi.org/10.1182/blood-2017-06-789669