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），目前仍无法治愈，其中MM尤其容易复发。我们的研究引入了一种新型小鼠模型，该模型具有活跃的RANK信号传导和TCL1癌基因，同时表现出CLL和MM的表型。在年轻小鼠中，TCL1和RANK表达促使CLL样B1淋巴细胞扩增，而MM则起源于B2细胞，在疾病后期占据主导地位，导致严重的疾病进展和死亡。诱导的MM模拟了人类疾病，表现出克隆性浆细胞扩增、副蛋白血症、贫血、肾脏和骨骼衰竭等特征，以及促进支持肿瘤微环境的关键免疫监视策略。这项研究阐明了RANK激活在B1和B2细胞中的不同影响，并强调了单一癌基因与联合癌基因在B细胞恶性肿瘤中的独特作用。我们还证明了人类MM细胞表达RANK，且在异种移植模型中抑制RANK信号传导可减缓MM进展。我们的研究为进一步探究RANK信号传导在B细胞转化及促肿瘤微环境形成中的作用提供了理论依据。
肿瘤(癌症)患者之家