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 XuFeng Chun Yang

Research output: Contribution to journalArticle

45 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- Asxl1 Y588X transgenic mouse model, Asxl1 Y588X Tg, to express a truncated FLAG-ASXL1 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 cKit 1 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. (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
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    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., ... 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