Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.
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作者：
编码 KMT2D（也称为 MLL2）甲基转移酶的基因突变高度复发，并且发生在弥漫性大 B 细胞淋巴瘤 (DLBCL) 和滤泡性淋巴瘤 (FL) 肿瘤发生的早期。然而，KMT2D 突变的功能后果及其在淋巴瘤发生中的作用尚不清楚。在这里，我们发现 FL/DLBCL 相关的 KMT2D 突变会损害 KMT2D 酶活性，导致生发中心 (GC) B 细胞和 DLBCL 细胞中整体 H3K4 甲基化减少。在 B 细胞发育早期（但不是在 GC 反应开始后）有条件地删除 Kmt2d，会导致 GC B 细胞增加并增强小鼠的 B 细胞增殖。在过度表达 BCL2 的小鼠中，这些小鼠会发展出类似于人类肿瘤的 GC 衍生淋巴瘤，Kmt2d 的基因消除会导致肿瘤发病率进一步增加。这些发现表明，KMT2D 作为一种肿瘤抑制基因，其早期丢失通过重塑癌症前体细胞的表观遗传景观来促进淋巴瘤的发生。根除 KMT2D 缺陷细胞可能代表针对早期致瘤事件的合理治疗方法。
Mutations in the gene encoding the KMT2D (also called MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of KMT2D mutations and their role in lymphomagenesis are unknown. Here we show that FL/DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B-cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B-cells and enhances B cell proliferation in mice. In mice overexpressing BCL2, which develop GC-derived lymphomas resembling human tumors, genetic ablation of Kmt2d leads to a further increase in tumor incidence. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach for targeting early tumorigenic events.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
30.8
作者：
Bereshchenko, OR;Gu, W;Dalla-Favera, R
通讯作者：
Dalla-Favera, R
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y