Abstract
Lymphomas arising from NK or γδ-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n=51), γδ-T-cell lymphomas (n=43) and their cell lines (n=9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of γδ-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.
Highlights
Lymphomas arising from NK or gd-T cells are very aggressive diseases and little is known regarding their pathogenesis
We validated the mutations detected from our whole-transcriptome sequencing (WTS) data that may be functionally significant including the mutations in FAS, TP53, BRAF, MAP2K1, CREBBP, EP300 and MLL2 genes, by Sanger sequencing on the corresponding genomic DNA (Supplementary Table 1)
All of the STAT3 and STAT5B single-nucleotide variant (SNV) were located in the Src homology 2 (SH2) domain, a domain critical for STAT activation[5]
Summary
To identify driver mutations of NKTCLs, whole-transcriptome sequencing (WTS), exome sequencing or targeted Sanger sequencing was applied on 53 NKTCL cases (Fig. 1a). (b) Representative flow cytometric plots showing the percentage of GFP þ cells days (day 0) and 12 days (day 9) post transduction of NKYS cells with EV or STAT3 shRNA after removing IL2 from the culture medium at day 0. (d) Representative FACS plots showing the percentage of GFP þ cells of YT cell line transduced with EV or STAT3 shRNA 3 days (day 0) or 15 days (day 12) post transduction. (h) Western blot images of STAT3 knock-down levels are shown for NKYS,YT and KAI3 cell lines on STAT3 shRNA transduced, GFP þ sorted cells post transduction with the EV (PLVTH) or STAT3 shRNA (S3S). KAI3 cells, which lack STAT3 or STAT5B mutations, with each of the STAT3 and STAT5B mutants and determined the % of GFP þ cells post transduction in regular time intervals. STAT3 A702T mutant showed only modest positive selection when compared with WT transduced cells
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