Friedman Daniel, Mehtani Drshika P, Vidler Jennifer B, Patten Piers E M, Hoogeboom Robbert
Department of Haemato-Oncology Comprehensive Cancer Centre, King's College London London UK.
Department of Haematological Medicine King's College Hospital London UK.
Hemasphere. 2024 Dec 17;8(12):e70064. doi: 10.1002/hem3.70064. eCollection 2024 Dec.
Chronic lymphocytic leukemia (CLL) is an incurable progressive malignancy of CD5 B cells with a birth rate between 0.1% and 1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood. Here, we stained peripheral blood CLL cells for ki67 and DNA content and found that CLL cells in G1-phase have a CXCR4CD5 phenotype, while CLL cells in S/G2/M-phase express high levels of both CXCR4 and CD5. Induction of proliferation in vitro using CD40L stimulation results in high ki67 levels in CXCR4CD5 cells with CXCR4 expression increasing as CLL cells progress through S and G2/M-phases, while CXCR4CD5 CLL cells remained quiescent. Dye dilution experiments revealed an accumulation of Ki67-divided cells in the CXCR4CD5 fraction. In Eµ-TCL1 transgenic mice, the CXCR4CD5 fraction expressed high levels of ki67 and was expanded in enlarged spleens of diseased animals. Human peripheral blood CXCR4CD5 CLL cells express increased levels of IgM and the chemokine receptors CCR7 and CXCR5 and migrate efficiently toward CCL21. We found higher levels of CXCR4 in patients with progressive disease and the CXCR4CD5 fraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of dividing CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcomes.
慢性淋巴细胞白血病（CLL）是一种无法治愈的CD5⁺B细胞进行性恶性肿瘤，每天的发生率占整个克隆的0.1%至1%。然而，增殖性CLL细胞的表型和功能特征仍未完全明确。在此，我们对外周血CLL细胞进行ki67和DNA含量染色，发现G1期的CLL细胞具有CXCR4⁺CD5⁺表型，而S/G2/M期的CLL细胞同时高表达CXCR4和CD5。使用CD40L刺激在体外诱导增殖，可使CXCR4⁺CD5⁺细胞中的ki67水平升高，随着CLL细胞进入S期和G2/M期，CXCR4表达增加，而CXCR4⁻CD5⁺ CLL细胞则保持静止。染料稀释实验显示，Ki67⁺分裂细胞在CXCR4⁺CD5⁺部分中积累。在Eµ-TCL1转基因小鼠中，CXCR4⁺CD5⁺部分高表达ki67，并在患病动物肿大的脾脏中扩增。人外周血CXCR4⁺CD5⁺ CLL细胞表达的IgM、趋化因子受体CCR7和CXCR5水平升高，并能有效地向CCL21迁移。我们发现进展性疾病患者的CXCR4水平更高，且在临床复发时CXCR4⁺CD5⁺部分会扩增。因此，本研究明确了分裂的CLL细胞的表型和功能特征，确定了一个新的亚克隆群体，该群体是CLL发病机制的基础，并可能推动临床结果。
