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 Wahlestedt, Mingjiang Xu and Feng-Chun Yang

Key points

  • Transgenic expression of ASXL1aa1-587 truncating protein in the hematopoietic system leads to diverse myeloid malignancies in mice.

  • ASXL1aa1-587 gains an interaction with BRD4 and Asxl1Y588XTg hematopoietic stem/progenitor cells are hyper sensitive to BET bromodomain inhibitors.


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-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 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.

  • Submitted June 8, 2017.
  • Accepted October 28, 2017.