5 years ago

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

Shi Chen, Hassan Al-Ali, Ines Lohse, Claes Wahlestedt, Shohei Yamamoto, Peng Zhang, Feng-Chun Yang, J William Harbour, Hui Yang, Stephen D Nimer, Mingjiang Xu, Michael A Durante, Zhaomin Li, Jianping Li, Yuan Zhou, Lingxiao Li, Matthew G Field, Ying Guo, Zizhen Chen, Stefan Kurtenbach, Zhuo Li
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-Seq analyses revealed that the ASXL1(aa1-587) 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 ASXL1(aa1-587) acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hyper-sensitivity 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.

Publisher URL: http://doi.org/10.1182/blood-2017-06-789669

DOI: 10.1182/blood-2017-06-789669

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