Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born/Divided and Older/Quiescent Cells

被引：145

作者：

Calissano, Carlo

Damle, Rajendra N. ^{[2
]}

Marsilio, Sonia

Yan, Xiao-Jie

Yancopoulos, Sophia

Hayes, Gregory ^{[4
]}

Emson, Claire ^{[4
]}

Murphy, Elizabeth J. ^{[4
,5
]}

Hellerstein, Marc K. ^{[4
]}

Sison, Cristina ^{[1
]}

Kaufman, Matthew S. ^{[6
]}

Kolitz, Jonathan E. ^{[2
]}

Allen, Steven L. ^{[2
]}

Rai, Kanti R. ^{[6
]}

Ivanovic, Ivana ^{[7
]}

Dozmorov, Igor M. ^{[7
]}

Roa, Sergio ^{[8
]}

Scharff, Matthew D. ^{[8
]}

Li, Wentian

Chiorazzi, Nicholas ^{[1
,2
,3
]}

机构：

[1] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Biostat Unit, Manhasset, NY 11030 USA

[2] N Shore LIJ Hlth Syst, N Shore Univ Hosp, Dept Med, Manhasset, NY 11030 USA

[3] Hofstra N Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY USA

[4] KineMed Inc, Emeryville, CA USA

[5] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[6] N Shore LIJ Hlth Syst, Long Isl Jewish Med Ctr, Dept Med, New Hyde Pk, NY USA

[7] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA

[8] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10467 USA

来源：

MOLECULAR MEDICINE | 2011年 / 17卷 / 11-12期

关键词：

B-CELLS; IN-VIVO; MONOCLONAL-ANTIBODY; CHEMOKINE RECEPTORS; EXPRESSION; PROLIFERATION; SURVIVAL; TURNOVER; CXCR4; DEATH;

D O I：

10.2119/molmed.2011.00360

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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

引用

页码：1374 / 1382

页数：9

共 59 条

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