Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born/Divided and Older/Quiescent Cells
Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born/Divided and Older/Quiescent Cells
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DOI：
10.2119/molmed.2011.00360
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发表时间：
2011-11-01
影响因子：
5.7
通讯作者：
Chiorazzi, Nicholas
中科院分区：
文献类型：
--
作者：
Calissano, Carlo;Damle, Rajendra N.;Chiorazzi, Nicholas
化疗方案根除癌症的失败通常是由于具有更危险的基因组异常或自我更新能力的较小亚克隆的生长。为了探索B细胞慢性淋巴细胞白血病（CLL）中的这种肿瘤内复杂性，我们通过量化氘（H-2）标记的细胞作为细胞分裂的指标来测量体内B细胞动力学。基于趋化因子（C-X-C基序）受体4（CXCR 4）和簇命名5（CD 5）的倒数密度分离CLL克隆揭示了CXCR 4（暗）CD 5（亮）（增殖）级分比CXCR 4（亮）CD 5（暗）（静止）级分含有更多的H-2标记的DNA，因此分裂的细胞。这种富集通过在相同组分中的两种细胞周期相关分子Ki-67和微小染色体维持蛋白6（MCM 6）的相对表达来证实。CXCR 4（dim）CD 5（bright）和CXCR 4（bright）CD 5（dim）组分之间的总体基因表达的比较表明，在增殖组分中促增殖和抗凋亡基因以及参与氧化损伤的基因的水平更高。一个扩展的免疫表型也被定义，提供了更广泛的表面分子特征的每个馏分。这些克隆内分析表明，CLL细胞生物学模型中，白血病克隆包含一系列细胞，从增殖部分，丰富的最近分裂的强大的细胞，淋巴组织移民，休息部分丰富的老年人，不太重要的细胞，需要迁移到淋巴组织或死亡。该模型还提出了几个目标，优先表达在两个人口适合治疗攻击。最后，这项研究为未来的分析奠定了基础，这些分析可能会对这种目前无法治愈的疾病的发展和克隆进化提供更有力的理解。(C)2011 Feinstein医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00360
The failure of chemotherapeutic regimens to eradicate cancers often results from the outgrowth of minor subclones with more dangerous genomic abnormalities or with self-renewing capacity. To explore such intratumor complexities in B-cell chronic lymphocytic leukemia (CLL), we measured B-cell kinetics in vivo by quantifying deuterium (H-2)-labeled cells as an indicator of a cell that had divided. Separating CLL clones on the basis of reciprocal densities of chemokine (C-X-C motif) receptor 4 (CXCR4) and cluster designation 5 (CD5) revealed that the CXCR4(dim)CD5(bright) (proliferative) fraction contained more H-2-labeled DNA and hence divided cells than the CXCR4(bright)CD5(dim) (resting) fraction. This enrichment was confirmed by the relative expression of two cell cycle-associated molecules in the same fractions, Ki-67 and minichromosome maintenance protein 6 (MCM6). Comparisons of global gene expression between the CXCR4(dim)CD5(bright) and CXCR4(bright)CD5(dim) fractions indicated higher levels of pro-proliferation and antiapoptotic genes and genes involved in oxidative injury in the proliferative fraction. An extended immunopheno-type was also defined, providing a wider range of surface molecules characteristic of each fraction. These intraclonal analyses suggest a model of CLL cell biology in which the leukemic clone contains a spectrum of cells from the proliferative fraction, enriched in recently divided robust cells that are lymphoid tissue emigrants, to the resting fraction enriched in older, less vital cells that need to immigrate to lymphoid tissue or die. The model also suggests several targets preferentially expressed in the two populations amenable for therapeutic attack. Finally, the study lays the groundwork for future analyses that might provide a more robust understanding of the development and clonal evolution of this currently incurable disease. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00360