外周T细胞淋巴瘤中鸟嘌呤交换因子VAV1的激活突变和易位。
Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas.
作者信息
Abate Francesco, da Silva-Almeida Ana C, Zairis Sakellarios, Robles-Valero Javier, Couronne Lucile, Khiabanian Hossein, Quinn S Aidan, Kim Mi-Yeon, Laginestra Maria Antonella, Kim Christine, Fiore Danilo, Bhagat Govind, Piris Miguel Angel, Campo Elias, Lossos Izidore S, Bernard Olivier A, Inghirami Giorgio, Pileri Stefano, Bustelo Xosé R, Rabadan Raul, Ferrando Adolfo A, Palomero Teresa
机构信息
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
出版信息
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):764-769. doi: 10.1073/pnas.1608839114. Epub 2017 Jan 6.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL.
外周T细胞淋巴瘤（PTCL）是一组异质性非霍奇金淋巴瘤，常与预后不良相关，其转化的遗传机制仍未完全明确。我们利用RNA测序和靶向测序，在PTCL中鉴定出一种由局灶性缺失驱动的可变剪接机制产生的复发性框内缺失（VAV1 Δ778-786）以及新型VAV1基因融合（VAV1-THAP4、VAV1-MYO1F和VAV1-S100A7）。从机制上讲，这些基因损伤导致VAV1催化依赖性（MAPK、JNK）和非催化依赖性（活化T细胞核因子，NFAT）VAV1效应通路的激活增加。这些结果支持VAV1信号在PTCL发病机制中起驱动致癌作用。
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