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Abstract：
Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-β1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-β1 axis.
摘要：
组蛋白甲基转移酶KMT2D是弥漫性大B细胞淋巴瘤（DLBCL）中最常见的突变基因之一，已被确定为重要的致病因子和预后标志物。然而,KMT2D突变与肿瘤微环境的生物学相关性尚待确定.通过全基因组/外显子组测序（WGS/WES）在334例患者中评估KMT2D突变，并通过靶向测序在427例新诊断的DLBCL患者中评估KMT2D突变。在所有761名DLBCL患者中，在143例（18.79％）患者中观察到KMT2D的体细胞突变，并且与晚期AnnArbor分期和MYC表达≥40％显着相关，以及较差的无进展生存期和总生存期。在B淋巴瘤细胞中，KMT2D的突变或敲低抑制组蛋白H3（H3K4）上赖氨酸4的甲基化，FBXW7表达下调，激活的NOTCH信号通路和下游MYC/TGF-β1，导致肿瘤诱导的调节性T细胞运输的改变。在皮下注射SU-DHL-4细胞建立的B淋巴瘤小鼠模型中，携带KMT2D突变的异种移植肿瘤呈现较低的H3K4甲基化，更高的调节性T细胞募集，从而通过FBXW7-NOTCH-MYC/TGF-β1轴与野生型KMT2D相比引起快速的肿瘤生长。
