Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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.
Cell Res. 2018 Feb;28(2):172-186. doi: 10.1038/cr.2017.146. Epub 2017 Nov 17.
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.
侵袭性自然杀伤细胞白血病（ANKL）是一种罕见的自然杀伤细胞肿瘤，在亚洲、中美洲和南美洲人群中更为普遍。患者通常在接受及时治疗管理后的数天至数月内死亡。在这里，我们通过整合全基因组、转录组和靶向测序、细胞因子阵列以及功能测定，首次对 ANKL 进行了全面研究。在 48%（29 例中的 14 例）的 ANKL 患者中鉴定出 JAK-STAT 通路突变，而所有检查患者的血浆中平均升高了 56 倍（P < 0.0001）的细胞外 STAT3 刺激物白细胞介素 10（IL10）。其他经常发生突变的基因包括 TP53（34%）、TET2（28%）、CREBBP（21%）和 MLL2（21%）。患者自然杀伤白血病细胞表现出 STAT3 磷酸化、MYC 表达和多个代谢途径转录活性的显著激活。功能上，STAT3 激活和 MYC 表达对 ANKL 细胞的增殖和存活至关重要。STAT 信号调节 MYC 转录程序，STAT 信号和 MYC 转录都需要维持核苷酸合成和糖酵解的激活。总之，JAK-STAT 通路代表了 ANKL 中基因组改变和 IL10 刺激的主要靶点。新发现的 JAK/STAT-MYC-生物合成轴可能为治疗这种亚型白血病的新型治疗策略的开发提供机会。
