B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment.

B 细胞恶性肿瘤，如慢性淋巴细胞白血病 （CLL） 和多发性骨髓瘤 （MM），仍然无法治愈，其中 MM 特别容易复发。我们的研究介绍了一种具有活性 RANK 信号传导和 TCL1 癌基因的新型小鼠模型，显示 CLL 和 MM 表型。在年轻小鼠中，TCL1 和 RANK 表达扩增了 CLL 样 B1 淋巴细胞，而 MM 起源于 B2 细胞，在后期变得占主导地位，导致严重的疾病进展和死亡。诱导的 MM 模拟人类疾病，表现出克隆性浆细胞扩增、副蛋白血症、贫血、肾和骨衰竭等特征，以及促进肿瘤支持微环境的关键免疫监视策略。本研究阐明了 RANK 激活在 B1 细胞和 B2 细胞中的不同影响，并强调了单个癌基因与联合癌基因在 B 细胞恶性肿瘤中的不同作用。我们还证明，人类 MM 细胞表达 RANK，并且抑制 RANK 信号传导可以减少异种移植模型中的 MM 进展。我们的研究为进一步研究 RANK 信号在 B 细胞转化和肿瘤促进微环境塑造中的影响提供了理论依据。