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

Carlo Calissano, Rajendra N. Damle, Sonia Marsilio, Xiao Jie Yan, Sophia Yancopoulos, Gregory Hayes, Claire Emson, Elizabeth J. Murphy, Marc K. Hellerstein, Cristina Sison, Matthew S. Kaufman, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Ivana Ivanovic, Igor M. Dozmorov, Sergio Roa, Matthew D. Scharff, Wentian Li, Nicholas Chiorazzi

Research output: Contribution to journalArticle

71 Scopus citations

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 ( 2H)-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 dimCD5 bright (proliferative) fraction contained more 2H-labeled DNA and hence divided cells than the CXCR4 brightCD5 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 dimCD5 bright and CXCR4 brightCD5 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. © 2011 The Feinstein Institute for Medical Research.

Original languageEnglish (US)
Pages (from-to)1374-1382
Number of pages9
JournalMolecular Medicine
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Calissano, C., Damle, R. N., Marsilio, S., Yan, X. J., Yancopoulos, S., Hayes, G., Emson, C., Murphy, E. J., Hellerstein, M. K., Sison, C., Kaufman, M. S., Kolitz, J. E., Allen, S. L., Rai, K. R., Ivanovic, I., Dozmorov, I. M., Roa, S., Scharff, M. D., Li, W., & Chiorazzi, N. (2011). Intraclonal complexity in chronic lymphocytic leukemia: Fractions enriched in recently born/divided and older/quiescent cells. Molecular Medicine, 17(11), 1374-1382. https://doi.org/10.2119/molmed.2011.00360