文章：

慢性淋巴细胞白血病B细胞克隆内复杂性特征：B细胞受体与其他刺激信号交互作用的潜在影响

Characterization of the Intraclonal Complexity of Chronic Lymphocytic Leukemia B Cells: Potential Influences of B-Cell Receptor Crosstalk with Other Stimuli

原文发布日期：25 September 2023

DOI: 10.3390/cancers15194706

类型: Article

开放获取: 是

英文摘要：

Chronic lymphocytic leukemia (CLL) clones contain subpopulations differing in time since the last cell division (“age”): recently born, proliferative (PF; CXCR4DimCD5Bright), intermediate (IF; CXCR4IntCD5Int), and resting (RF; CXCR4BrightCD5Dim) fractions. Herein, we used deuterium (2H) incorporation into newly synthesized DNA in patients to refine the kinetics of CLL subpopulations by characterizing two additional CXCR4/CD5 fractions, i.e., double dim (DDF; CXCR4DimCD5Dim) and double bright (DBF; CXCR4BrightCD5Bright); and intraclonal fractions differing in surface membrane (sm) IgM and IgD densities. Although DDF was enriched in recently divided cells and DBF in older cells, PF and RF remained the most enriched in youngest and oldest cells, respectively. Similarly, smIgMHighand smIgDHighcells were the youngest, and smIgMLowand smIgDLowwere the oldest, when using smIG levels as discriminator. Surprisingly, the cells closest to the last stimulatory event bore high levels of smIG, and stimulating via TLR9 and smIG yielded a phenotype more consistent with the in vivo setting. Finally, older cells were less sensitive to in vivo inhibition by ibrutinib. Collectively, these data define additional intraclonal subpopulations with divergent ages and phenotypes and suggest that BCR engagement alone is not responsible for the smIG levels found in vivo, and the differential sensitivity of distinct fractions to ibrutinib might account, in part, for therapeutic relapse.

摘要翻译： 

慢性淋巴细胞白血病（CLL）克隆包含自上次细胞分裂以来时间不同（即“年龄”不同）的亚群：近期增殖的增殖性组分（PF；CXCR4DimCD5Bright）、中间组分（IF；CXCR4IntCD5Int）以及静息组分（RF；CXCR4BrightCD5Dim）。本研究通过氘（2H）标记患者新合成DNA的方法，进一步解析了CLL亚群的动力学特征：鉴定了两个额外的CXCR4/CD5组分——双低表达组分（DDF；CXCR4DimCD5Dim）与双高表达组分（DBF；CXCR4BrightCD5Bright）；以及根据表面膜（sm）IgM与IgD表达密度区分的克隆内组分。尽管DDF富集于近期分裂的细胞，DBF富集于较老的细胞，但PF与RF仍分别是新生细胞与最老细胞中富集程度最高的组分。类似地，当以smIG水平作为区分标准时，smIgM高表达与smIgD高表达细胞最为年轻，而smIgM低表达与smIgD低表达细胞最为年老。值得注意的是，最接近上次刺激事件的细胞携带高水平的smIG，且通过TLR9与smIG途径刺激产生的表型更符合体内实际情况。最后，较老的细胞对伊布替尼的体内抑制作用敏感性较低。总体而言，这些数据定义了具有不同年龄与表型的额外克隆内亚群，提示单纯BCR结合并不能解释体内观察到的smIG水平，而不同组分对伊布替尼的敏感性差异可能部分解释了治疗后的复发现象。

原文链接：

Characterization of the Intraclonal Complexity of Chronic Lymphocytic Leukemia B Cells: Potential Influences of B-Cell Receptor Crosstalk with Other Stimuli