Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

Abstract

Lymphomas arising from NK or gd-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 ¼ 51), gd-T-cell lymphomas (n ¼ 43) and their cell lines (n ¼ 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gd-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.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…STATs display a tight regulation of the expression of genes whose protein products regulate critical processes such as proliferation, survival, differentiation, senescence, metabolism, angiogenesis, and invasion [123]. Constitutive activation of STAT3/5 is commonly found in MPN and PTCL [20,124]. Consistent with the prediction that oncogenic transcription factors are triggered downstream of many activated drivers, STATs are activated much more commonly than any single genetic driver mutation [125].…”

“…Importantly, ALK − ALCL is associated with STAT3 activation [64] and recurrent, somatic activating mutations in the closely related STAT5B gene were reported. The STAT5B N642H mutation occurs with the highest frequency in PTCL, whereby most mutations cluster in the SH 2 and C-terminal transactivation domain [70,75,78–82]. A recent study found that ~70% of T-PLL patients carry JAK-STAT hyperactivating mutations [70].…”

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

“…It is also important for lymphoid cell development ( 9 ): STAT5 is constitutively active in a plethora of lymphoid malignancies ( 10 ). Recent studies have described somatic Stat5b mutations as active drivers of lymphoid malignancies ( 11,12 ), and considerable efforts are under way to develop STAT5 inhibitors. Such inhibitors will not only target malignant hematopoietic cells but will also have severe consequences for immune functions that depend on the activation of STAT5 by cytokines.…”

High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia

“…1 T-LGL leukemia have also been seen in various T-cell neoplasms, including gd hepatosplenic T-cell lymphoma, 13 T-cell acute lymphoblastic leukemia, 14,15 T-cell prolymphocytic leukemia, 16 type II enteropathy-associated T-cell lymphoma, 17 and extranodal NK/T-cell lymphoma, 18 suggesting that these are shared with other T-cell malignancies. The analyses of STAT5 target genes with chromatin immunoprecipitation sequencing have shown that STAT5B is a key factor in T-cell development, binding to molecules such as DOCK8, SNX9, FOXP3, and IL2RA.…”