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.

引用

共 64 条

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