Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells.

摘要: The failure of chemotherapeutic regimens to eradicate cancers often results from the outgrowth minor subclones with more dangerous genomic abnormalities or self-renewing capacity. To explore such intratumor complexities in B-cell chronic lymphocytic leukemia (CLL), we measured kinetics vivo by quantifying deuterium (2H)-labeled cells as an indicator a cell that had divided. Separating CLL clones on basis reciprocal densities chemokine (C-X-C motif) receptor 4 (CXCR4) and cluster designation 5 (CD5) revealed CXCR4dimCD5bright (proliferative) fraction contained 2H-labeled DNA hence divided than CXCR4brightCD5dim (resting) fraction. This enrichment was confirmed relative expression two cycle-associated molecules same fractions, Ki-67 minichromosome maintenance protein 6 (MCM6). Comparisons global gene between fractions indicated higher levels pro-proliferation antiapoptotic genes involved oxidative injury proliferative An extended immunophenotype also defined, providing wider range surface characteristic each These intraclonal analyses suggest model biology which leukemic clone contains spectrum fraction, enriched recently robust are lymphoid tissue emigrants, resting older, less vital need immigrate die. suggests several targets preferentially expressed populations amenable for therapeutic attack. Finally, study lays groundwork future might provide understanding development clonal evolution this currently incurable disease.