期刊
CELL RESEARCH
卷 28, 期 2, 页码 172-186出版社
SPRINGERNATURE
DOI: 10.1038/cr.2017.146
关键词
aggressive NK-cell leukemia; genomic landscape; IL-10; JAK/STAT pathway; MYC activation; nucleotide synthesis; glycolysis
类别
资金
- National Natural Science Foundation of China [81570196, 81425003, 81670152, 81600120, 81300410, 81500100, 81400122]
- National Key Basic Research Program of China [2014CB542001]
- Key Program of the National Natural Science Foundation of China [81230052]
- Key Research Program of the Chinese Academy of Sciences (Precious Medicine Research in Chinese Population) [KJZD-EW-L14-3]
- National High Technology Research and Development Program of China (863 program) [2012AA02A507, 2014AA020532]
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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