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

Can Küçük; Bei Jiang; Xiaozhou Hu; Wenyan Zhang; John K.C. Chan; Wenming Xiao; Nathan Lack; Can Alkan; John C. Williams; Kendra N. Avery; Painar Kavak; Anna Scuto; Emel Sen; Philippe Gaulard; Lou Staudt; Javeed Iqbal; Weiwei Zhang; Adam Cornish; Qiang Gong; Qunpei Yang; Hong Sun; Francesco D'Amore; Sirpa Leppä; Weiping Liu; Kai Fu; Laurence De Leval; Timothy McKeithan; Wing C. Chan

doi:10.1038/ncomms7025

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

Can Küçük, Bei Jiang, Xiaozhou Hu, Wenyan Zhang, John K.C. Chan, Wenming Xiao, Nathan Lack, Can Alkan, John C. Williams, Kendra N. Avery, Painar Kavak, Anna Scuto, Emel Sen, Philippe Gaulard, Lou Staudt, Javeed Iqbal, Weiwei Zhang, Adam Cornish, Qiang Gong, Qunpei YangHong Sun, Francesco D'Amore, Sirpa Leppä, Weiping Liu, Kai Fu, Laurence De Leval, Timothy McKeithan, Wing C. Chan

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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.

Original language	English (US)
Article number	6025
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7025
State	Published - Jan 2015

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Küçük, C., Jiang, B., Hu, X., Zhang, W., Chan, J. K. C., Xiao, W., Lack, N., Alkan, C., Williams, J. C., Avery, K. N., Kavak, P., Scuto, A., Sen, E., Gaulard, P., Staudt, L., Iqbal, J., Zhang, W., Cornish, A., Gong, Q., ... Chan, W. C. (2015). Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nature communications, 6, [6025]. https://doi.org/10.1038/ncomms7025

Küçük, C, Jiang, B, Hu, X, Zhang, W, Chan, JKC, Xiao, W, Lack, N, Alkan, C, Williams, JC, Avery, KN, Kavak, P, Scuto, A, Sen, E, Gaulard, P, Staudt, L, Iqbal, J , Zhang, W, Cornish, A, Gong, Q, Yang, Q, Sun, H, D'Amore, F, Leppä, S, Liu, W, Fu, K, De Leval, L, McKeithan, T & Chan, WC 2015, 'Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells', Nature communications, vol. 6, 6025. https://doi.org/10.1038/ncomms7025

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

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.",

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T1 - Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

AU - Küçük, Can

AU - Jiang, Bei

AU - Hu, Xiaozhou

AU - Zhang, Wenyan

AU - Chan, John K.C.

AU - Xiao, Wenming

AU - Lack, Nathan

AU - Alkan, Can

AU - Williams, John C.

AU - Avery, Kendra N.

AU - Kavak, Painar

AU - Scuto, Anna

AU - Sen, Emel

AU - Gaulard, Philippe

AU - Staudt, Lou

AU - Iqbal, Javeed

AU - Zhang, Weiwei

AU - Cornish, Adam

AU - Gong, Qiang

AU - Yang, Qunpei

AU - Sun, Hong

AU - D'Amore, Francesco

AU - Leppä, Sirpa

AU - Liu, Weiping

AU - Fu, Kai

AU - De Leval, Laurence

AU - McKeithan, Timothy

AU - Chan, Wing C.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

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

Abstract

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