B细胞本源的RANK信号通路与TCL1协作诱导系依赖性B细胞转化

B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation

Blood Cancer Journal

影响因子:11.6

分区:医学1区 Top / 血液学1区肿瘤学1区

发表日期:2024 Aug 28

作者: Lisa Pfeuffer, Viola Siegert, Julia Frede, Leonie Rieger, Riccardo Trozzo, Niklas de Andrade Krätzig, Sandra Ring, Shamim Sarhadi, Nicole Beck, Stefan Niedermeier, Mar Abril-Gil, Mohamed Elbahloul, Marianne Remke, Katja Steiger, Ruth Eichner, Julia Jellusova, Roland Rad, Florian Bassermann, Christof Winter, Jürgen Ruland, Maike Buchner

DOI: 10.1038/s41408-024-01123-6

摘要

B细胞恶性肿瘤，如慢性淋巴细胞性白血病（CLL）和多发性骨髓瘤（MM），至今仍无法治愈，其中MM特别容易复发。我们的研究引入一种新型的携带活性RANK信号通路和TCL1癌基因的小鼠模型，表现出CLL和MM的表型。在年轻的小鼠中，TCL1和RANK的表达扩展了CLL样B1淋巴细胞，而MM则起源于B2细胞，在后期成为主要细胞类型，导致严重的疾病进展和死亡。诱导的MM模拟人类疾病，表现出克隆浆细胞扩增、蛋白质血症、贫血、肾脏和骨骼衰竭等特征，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和B2细胞中的差异性影响，并强调单一与联合癌基因在B细胞恶性肿瘤中的不同作用。我们还展示了人类MM细胞表达RANK，抑制RANK信号可以在异种移植模型中减少MM的发展。我们的研究为进一步探索RANK信号在B细胞转化及肿瘤促进微环境形成中的作用提供了理论依据。

Abstract

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.