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

被引:0
作者
Can Küçük
Bei Jiang
Xiaozhou Hu
Wenyan Zhang
John K. C. Chan
Wenming Xiao
Nathan Lack
Can Alkan
John C. Williams
Kendra N. Avery
Pınar 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
机构
[1] City of Hope Medical Center,Department of Pathology
[2] West China Hospital of Sichuan University,Department of Pathology
[3] Queen Elizabeth Hospital,Department of Pathology
[4] National Center for Toxicological Research,Division of Bioinformatics and Biostatistics
[5] Food and Drug Administration,Department of Pharmacology
[6] Koc University,Department of Computer Engineering
[7] Bilkent University,Department of Molecular Medicine
[8] Beckman Research Institute of City of Hope,Department of Computer Engineering
[9] Boğaziçi University,Département de Pathologie
[10] Groupe Henri-Mondor Albert-Chenevier,Department of Pathology and Microbiology
[11] Inserm U955,Department of Genetics
[12] Université Paris Est,Department of Hematology
[13] Molecular Biology of Lymphoid Malignancies Section,Department of Oncology
[14] Center for Cancer Research,undefined
[15] National Cancer Institute,undefined
[16] University of Nebraska Medical Center,undefined
[17] Cell Biology and Anatomy,undefined
[18] University of Nebraska Medical Center,undefined
[19] Beijing Institute of Genomics,undefined
[20] Chinese Academy of Sciences,undefined
[21] Aarhus University Hospital,undefined
[22] Helsinki University Central Hospital,undefined
[23] Pathologie Clinique Institut,undefined
[24] Universitaire de Pathologie rue du Bugnon 25,undefined
来源
Nature Communications | / 6卷
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摘要
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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