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Cell Res. 2018 Feb;28(2):172-186. doi: 10.1038/cr.2017.146. Epub 2017 Nov 17.

Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia.

Huang L1, Liu D2, Wang N1, Ling S2,3, Tang Y1, Wu J2, Hao L2,4,3, Luo H1, Hu X1, Sheng L1, Zhu L1, Wang D1, Luo Y1, Shang Z1, Xiao M1, Mao X1, Zhou K1, Cao L2,3, Dong L2, Zheng X2,4, Sui P2,4, He J2, Mo S2,4, Yan J2, Ao Q5, Qiu L6, Zhou H7, Liu Q7, Zhang H8, Li J9, Jin J10, Fu L11, Zhao W12, Chen J13, Du X14, Qing G15, Liu H15, Liu X2,4, Huang G16,17, Ma D18,19, Zhou J1,6,19, Wang QF2,6,4.

Author information

1
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
2
Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
3
Genome Wisdom Inc., Beijing 100195, China.
4
University of Chinese Academy of Sciences, Beijing 100049, China.
5
Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
6
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
7
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
8
Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China.
9
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University and Jiangsu Province Hospital, Nanjing, Jiangsu 210029, China.
10
Department of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310003, China.
11
Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
12
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
13
Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
14
Department of Hematology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
15
Medical Research Institute, Wuhan University, Wuhan, Hubei 430071, China.
16
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
17
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
18
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
19
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.

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.

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