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

• Published in: Blood Vol. 131; no. 3; pp. 328 - 341
• Main Authors: Yang, Hui, Kurtenbach, Stefan, Guo, Ying, Lohse, Ines, Durante, Michael A., Li, Jianping, Li, Zhaomin, Al-Ali, Hassan, Li, Lingxiao, Chen, Zizhen, Field, Matthew G., Zhang, Peng, Chen, Shi, Yamamoto, Shohei, Li, Zhuo, Zhou, Yuan, Nimer, Stephen D., Harbour, J. William, Wahlestedt, Claes, Xu, Mingjiang, Yang, Feng-Chun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-01-2018; American Society of Hematology
• Subjects: Animals; Bone Marrow Cells - metabolism; Cell Differentiation - genetics; Cell Lineage - genetics; Chromatin - metabolism; Gain of Function Mutation - genetics; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells - metabolism; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Mice, Transgenic; Myeloid Neoplasia; Nuclear Proteins - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Proto-Oncogene Proteins c-kit - metabolism; Proto-Oncogene Proteins c-vav - metabolism; Repressor Proteins - genetics; Transcription Factors - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-06-789669

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 cKit+ 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.
•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 hypersensitive to BET bromodomain inhibitors.