The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.
The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.
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DOI：
10.1038/nm.3943
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发表时间：
2015-10
期刊：
影响因子：
82.9
通讯作者：
Wendel HG
中科院分区：
文献类型：
--
作者：
Ortega-Molina A;Boss IW;Canela A;Pan H;Jiang Y;Zhao C;Jiang M;Hu D;Agirre X;Niesvizky I;Lee JE;Chen HT;Ennishi D;Scott DW;Mottok A;Hother C;Liu S;Cao XJ;Tam W;Shaknovich R;Garcia BA;Gascoyne RD;Ge K;Shilatifard A;Elemento O;Nussenzweig A;Melnick AM;Wendel HG
赖氨酸特异性组蛋白甲基转移酶KMT2D是滤泡性淋巴瘤（FL）和弥漫性大B细胞淋巴瘤（DLBCL）中最常见的突变基因之一。然而，KMT2D突变对淋巴瘤发展的生物学影响尚不清楚。在这里，我们表明KMT2D作为一种真正的肿瘤抑制因子，其在B细胞中的基因消融促进了小鼠淋巴瘤的发展。KMT2D缺陷还会延迟生发中心（GC）的内化，阻碍B细胞分化和类开关重组（CSR）。综合基因组分析表明，KMT2D影响H3K4甲基化和一组特定基因的表达，包括CD40、JAK-STAT、toll样受体和B细胞受体途径中的基因。值得注意的是，其他KMT2D靶基因包括经常突变的肿瘤抑制基因，如TNFAIP3、SOCS3和TNFRSF14。因此，KMT2D突变可能通过干扰控制B细胞激活途径的肿瘤抑制基因的表达来促进恶性生长。
The lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). However, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center (GC) involution, impedes B cell differentiation and class switch recombination (CSR). Integrative genomic analyses indicate that KMT2D affects H3K4 methylation and expression of a specific set of genes including those in the CD40, JAK-STAT, Toll-like receptor, and B cell receptor pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3, and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell activating pathways.