Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma
Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma
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DOI：
10.1038/leu.2015.328
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发表时间：
2016-04-01
期刊：
影响因子：
11.4
通讯作者：
Hansmann, M-L
中科院分区：
文献类型：
--
作者：
Hartmann, S.;Schuhmacher, B.;Hansmann, M-L
结节性淋巴细胞为主型霍奇金淋巴瘤（NLPHL）是霍奇金淋巴瘤（HL）的一个亚型，其特征是肿瘤细胞（淋巴细胞为主型（LP）细胞）含量低。大约10%的患者会转化为弥漫性大B细胞淋巴瘤（DLBCL）。我们进行了全基因组突变分析的DLBCL组件从两个复合淋巴瘤组成的克隆相关的NLPHL和DLBCL作为一种手段，以确定候选的肿瘤抑制基因和癌基因在NLPHL。对LP细胞的DLBCL的选定突变的分析揭示，大多数突变也存在于LP细胞中，表明两种组分之间的密切关系。通过靶向超深度测序对NLPHL中的62个选定基因进行分析，发现了三个新的高度复发突变的基因（每个突变的情况类似于50%），即DUSP2，SGK1和JUNB。SGK1在原发性NLPHL病例的LP细胞和NLPHL细胞系DEV中表达。SGK1抑制剂的施用诱导NLPHL细胞系DEV和DLBCL细胞系Farage中的细胞凋亡，表明SGK1在LP和DLBCL细胞中的致病作用。总之，本研究将SGK1、DUSP2和JUNB确定为NLPHL发病机制中的新关键参与者。
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in similar to 50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.