Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B-cell lymphoma (DLBCL). However, the premalignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to 4 hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1, and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivo promoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). As with MCD, these premalignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, displayed a de novo dependence on Tlr9, and were more sensitive to inhibition of Bruton's tyrosine kinase. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all 4 genetic lesions showed a >50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCBs as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.

中文翻译：

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由侵袭性淋巴瘤的标志性遗传病变引起的自发性脾生发中心的异常扩张。

在弥漫性大 B 细胞淋巴瘤 (DLBCL) 的侵袭性 MCD/C5 遗传亚类中发现了独特的分子漏洞。然而，表现出类似 MCD 依赖性的癌前起源细胞仍然难以捉摸。在这项研究中，我们检查了携带最多 4 个 MCD 标志性遗传损伤的动物，包括 Myd88 和 Cd79b 的功能获得性突变、Prdm1 缺失和 BCL2 过度表达。我们发现这些等位基因组合的体内表达促进了自发脾生发中心（GC）中 B 细胞的细胞内在积累。与 MCD 一样，这些癌前 B 细胞富集 B 细胞受体 (BCR)，并具有自身反应性证据，表现出对 Tlr9 的从头依赖，并且对布鲁顿酪氨酸激酶的抑制更敏感。突变的自发脾 GC B 细胞 (GCB) 显示增殖和 IRF4 表达增加。携带全部 4 种遗传病变的小鼠表现出自发性脾 GC 扩增 > 50 倍，表现出异常组织学特征和暗区免疫表型，并随着年龄的增长在脾脏中发展为 DLBCL。因此，通过结合与 MCD 相关的多个标志性遗传改变，我们的研究将异常的自发性脾 GCB 确定为这种侵袭性淋巴瘤基因亚型的可能起源细胞。