Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2–driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life–derived B1a cells, can be an effective therapeutic strategy to treat MCL.

中文翻译：

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细胞周期蛋白 D2 过表达驱动 B1a 衍生的小鼠 MCL 样淋巴瘤

套细胞淋巴瘤 (MCL) 是一种侵袭性 B 细胞淋巴瘤，长期总生存率较差。目前，由于缺乏良好的体内模型，MCL 潜在治愈方法的研究和开发受到阻碍。MCL 的特点是CCND1或CCND2的反复易位，分别导致细胞周期调节因子细胞周期蛋白 D1 或 D2 的过表达。在这里，我们首次表明，细胞周期蛋白 D2 的造血特异性激活足以驱动小鼠 MCL 样淋巴瘤的发展。此外，我们证明细胞周期蛋白 D2 过表达可以与 p53 的缺失协同作用，形成侵袭性和可移植的 MCL 样淋巴瘤。引人注目的是，细胞周期蛋白 D2 驱动的淋巴瘤显示出与 B1a B 细胞的转录、免疫表型和功能相似性。这些 MCL 样淋巴瘤具有 B1a 特异性 B 细胞受体 (BCR)，显示出升高的 BCR 和 NF-κB 通路激活，并显示出增加的 MALT1 蛋白酶活性。最后，我们提供临床前证据表明抑制 MALT1 蛋白酶活性，这对于早期生命衍生的 B1a 细胞的发育至关重要，