@article{dda21abd726943ed9170c9b9353f441b,
title = "Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia",
abstract = "Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.",
keywords = "IL-10, JAK/STAT pathway, MYC activation, aggressive NK-cell leukemia, genomic landscape, glycolysis, nucleotide synthesis",
author = "Liang Huang and Dan Liu and Na Wang and Shaoping Ling and Yuting Tang and Jun Wu and Lingtong Hao and Hui Luo and Xuelian Hu and Lingshuang Sheng and Lijun Zhu and Di Wang and Yi Luo and Zhen Shang and Min Xiao and Xia Mao and Kuangguo Zhou and Lihua Cao and Lili Dong and Xinchang Zheng and Pinpin Sui and Jianlin He and Shanlan Mo and Jin Yan and Qilin Ao and Lugui Qiu and Hongsheng Zhou and Qifa Liu and Hongyu Zhang and Jianyong Li and Jie Jin and Li Fu and Weili Zhao and Jieping Chen and Xin Du and Guoliang Qing and Hudan Liu and Xin Liu and Gang Huang and Ding Ma and Jianfeng Zhou and Wang, {Qian Fei}",
note = "Funding Information: We thank all the faculties and staffs in the Clinical and Laboratory Unit of the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology for their clinical and technical support; the Core Genomic Facility of Beijing Institute of Genomics, Chinese Academy of Sciences for the construction and sequencing of libraries; Drs Qing Li and Jiguang Wang for critical reading and valuable comments on the manuscript; Dr Kai Fu for providing the cell line YT. This study was supported by the National Natural Science Foundation of China (81570196 to JZ, 81425003 to QW, 81670152 to Liang H, 81600120 to NW, 81300410 to DW, 81500100 to YL and 81400122 to KZ), the National Key Basic Research Program of China (2014CB542001 to QW), the Key Program of the National Natural Science Foundation of China (81230052 to JZ), the Key Research Program of the Chinese Academy of Sciences (Precious Medicine Research in Chinese Population; KJZD-EW-L14-3 to QW), and the National High Technology Research and Development Program of China (863 program; 2012AA02A507 to JZ and 2014AA020532 to Liang H). Publisher Copyright: {\textcopyright} 2018 IBCB, SIBS, CAS All rights reserved.",
year = "2018",
month = feb,
day = "1",
doi = "10.1038/cr.2017.146",
language = "English (US)",
volume = "28",
pages = "172--186",
journal = "Cell Research",
issn = "1001-0602",
publisher = "Nature Publishing Group",
number = "2",
}