Abstract
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 ((2)H)-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 (2)H-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 immunophenotype 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.
Highlights
IntroductionIs a relatively frequent, incurable B-cell malignancy [1,2]
Chronic lymphocytic leukemia (CLL)is a relatively frequent, incurable B-cell malignancy [1,2]
CLL clones can be divided into distinct fractions on the basis of inverse surface expression of CXCR4 and cluster designation 5 (CD5)
Summary
Is a relatively frequent, incurable B-cell malignancy [1,2]. Even though some patients live for long periods with the disease, many undergo progressive decline, leading to demise. Progression to a more aggressive disease is often associated with genomic changes [3], suggesting that clonal evolution is a key factor in the disease. We previously found that CLL clones are composed of subpopulations of cells that proliferate at different rates [4], as measured by in vivo deuterium (2H)incorporation into newly synthesized DNA of dividing cells [5,6]. The most proliferative fraction of a cancer clone is of major interest for several reasons.
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