@article{dace9dc7e0174dbe89fd867dad28c909,
title = "Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies",
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.",
author = "Hui Yang and Stefan Kurtenbach and Ying Guo and Ines Lohse and Durante, {Michael A.} and Jianping Li and Zhaomin Li and Hassan Al-Ali and Lingxiao Li and Zizhen Chen and Field, {Matthew G.} and Peng Zhang and Shi Chen and Shohei Yamamoto and Zhuo Li and Yuan Zhou and Nimer, {Stephen D.} and {William Harbour}, J. and Claes Wahlestedt and Mingjiang Xu and Yang, {Feng Chun}",
note = "Funding Information: This work was supported by grants from the National Institutes of Health, National Cancer Institute (CA172408 and CA185751) (F.-C.Y. and M.X.) and the National Heart, Lung, and Blood Institute (HL112294) (M.X.), Chinese Academy of Medical Sciences (202016-I2M-2-001) (Y.Z.), the Alcon Research Institute (J.W.H.), the Sylvester Comprehensive Cancer Center (PG006470 [F.-C.Y., J.W.H.]), the University of Miami Sheila and David Fuente Graduate Program in Cancer Biology (M.G.F. and M.A.D.), and the Center for Computational Science Fellowship (M.G.F. and M.A.D), and by a generous gift from Dr. Mark J. Daily (J.W.H.). Epigenetic drug discovery work in the Wahlestedt laboratory is currently funded by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (AA023781) and the National Institute on Drug Abuse (DA042650). EP-11313 was generously provided by Epigenetix Inc. The Bascom Palmer Eye Institute also received funding from the National Institutes of Health National Eye Institute (Core Grant P30EY014801), Department of Defense (329 Grant #W81XWH-13-1-0048), and a Research to Prevent Blindness Unrestricted Grant. Funding Information: The authors thank the Drug Discovery Core, Satellite Histological Core, Flow Cytometry Core, Oncogenomics Core, and Biostatistics and Bio-informatics Core Facilities of Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. This work was supported by grants from the National Institutes of Health, National Cancer Institute (CA172408 and CA185751) (F.-C.Y. and M.X.) and the National Heart, Lung, and Blood Institute (HL112294) (M.X.), Chinese Academy of Medical Sciences (202016-I2M-2-001) (Y.Z.), the Alcon Research Institute (J.W.H.), the Sylvester Comprehensive Cancer Center (PG006470 [F.-C.Y., J.W.H.]), the University of Miami Sheila and David Fuente Graduate Program in Cancer Biology (M.G.F. and M.A.D.), and the Center for Computational Science Fellowship (M.G.F. and M.A.D), and by a generous gift from Dr. Mark J. Daily (J.W.H.). Epigenetic drug discovery work in the Wahlestedt laboratory is currently funded by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (AA023781) and the National Institute on Drug Abuse (DA042650). EP-11313 was generously provided by Epigenetix Inc. The Bascom Palmer Eye Institute also received funding from the National Institutes of Health National Eye Institute (Core Grant P30EY014801), Department of Defense (329 Grant #W81XWH-13-1-0048), and a Research to Prevent Blindness Unrestricted Grant. Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology.",
year = "2018",
month = jan,
day = "18",
doi = "10.1182/blood-2017-06-789669",
language = "English (US)",
volume = "131",
pages = "328--341",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "3",
}