Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
School of Medicine, Technische Universität München, Munich, Germany.
Leukemia. 2021 Oct;35(10):2895-2905. doi: 10.1038/s41375-021-01376-1. Epub 2021 Aug 6.
Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4 B cells enriched a transcriptional signature from patients with Richter's syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype.
异常的 CXCR4 活性已被牵涉到淋巴瘤的发病机制、疾病进展和对治疗的耐药性中。我们使用一种具有功能获得性 CXCR4 突变（CXCR4）的小鼠模型，该突变可过度激活 CXCR4 信号，将 CXCR4 鉴定为多个关键致癌途径的关键激活剂。CXCR4 的过度激活导致过渡性 B1 淋巴细胞的扩增，而过渡性 B1 淋巴细胞是慢性淋巴细胞白血病（CLL）的前体。事实上，CXCR4 的过度激活导致了小鼠 Eµ-TCL1 CLL 模型中疾病发病的显著加速和更具侵袭性的表型。过度激活的 CXCR4 信号与 TCL1 合作，导致 B 细胞中出现独特的致癌转录程序，其特征是与 PLK1/FOXM1 相关的途径。相应地，Eµ-TCL1;CXCR4 B 细胞富集了来自 Richter 综合征患者的转录特征，Richter 综合征是 CLL 的一种侵袭性转化。值得注意的是，侵袭性淋巴瘤中 MYC 的激活与 CXCR4 表达的增加有关。与这一发现一致，Eµ-Myc 小鼠（一种侵袭性 B 细胞癌模型）中额外的过度激活的 CXCR4 信号并不影响生存。总之，我们在这里确定 CXCR4 的过度激活是侵袭性淋巴瘤表型的共同驱动因素。
