@article{7ff5311700a34262a469fd0ded5982da,
title = "Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy",
abstract = "ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations.",
author = "Peng Zhang and Fuhong He and Jie Bai and Shohei Yamamoto and Shi Chen and Lin Zhang and Mengyao Sheng and Lei Zhang and Ying Guo and Na Man and Hui Yang and Suyun Wang and Tao Cheng and Nimer, {Stephen D.} and Yuan Zhou and Mingjiang Xu and Wang, {Qian Fei} and Yang, {Feng Chun}",
note = "Funding Information: This work was supported by grants from the NIH (CA172408 and CA185751, to FCY and MX); the Leukemia and Lymphoma Society Specialized Center of Research grant (to FCY, MX, and SDN); the National Natural Science Foundation of China (91731302,toQFW;81570113,toYZ;81421002,toTC;81470302, to LZ; and 81470340, to FH); the Social Development Project of Jiangsu Province (CXTDA2017014); and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (to FH). We thank the members of the Satellite Histological Core, Flow Cytometry Core, and Oncogenomics Core Facilities of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. Funding Information: This work was supported by grants from the NIH (CA172408 and CA185751, to FCY and MX); the Leukemia and Lymphoma Society Specialized Center of Research grant (to FCY, MX, and SDN); the National Natural Science Foundation of China (91731302, to QFW; 81570113, to YZ; 81421002, to TC; 81470302, to LZ; and 81470340, to FH); the Social Development Project of Jiangsu Province (CXTDA2017014); and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (to FH). We thank the members of the Satellite Histological Core, Flow Cytometry Core, and Oncogenomics Core Facilities of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. Publisher Copyright: Copyright 2018, American Society for Clinical Investigation.",
year = "2018",
month = dec,
day = "3",
doi = "10.1172/JCI121366",
language = "English (US)",
volume = "128",
pages = "5383--5398",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",
}