The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia

被引：694

作者：

Herishanu, Yair ^{[1
]}

Perez-Galan, Patricia ^{[1
]}

Liu, Delong ^{[2
]}

Biancotto, Angelique ^{[3
]}

Pittaluga, Stefania ^{[4
]}

Vire, Berengere ^{[1
]}

Gibellini, Federica ^{[1
]}

Njuguna, Ndegwa ^{[1
]}

Lee, Elinor ^{[1
]}

Stennett, Lawrence ^{[1
]}

Raghavachari, Nalini

Liu, Poching

McCoy, J. Philip ^{[3
]}

Raffeld, Mark ^{[4
]}

Stetler-Stevenson, Maryalice ^{[4
]}

Yuan, Constance ^{[4
]}

Sherry, Richard ^{[5
]}

Arthur, Diane C. ^{[4
]}

Maric, Irina ^{[6
]}

White, Therese ^{[7
]}

Marti, Gerald E. ^{[8
]}

Munson, Peter ^{[2
]}

Wilson, Wyndham H. ^{[8
]}

Wiestner, Adrian ^{[1
]}

机构：

[1] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA

[2] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA

[3] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA

[4] NCI, Pathol Lab, Bethesda, MD 20892 USA

[5] NCI, Surg Branch, Bethesda, MD 20892 USA

[6] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA

[7] NCI, Ctr Canc Res, Bethesda, MD 20892 USA

[8] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA

来源：

BLOOD | 2011年 / 117卷 / 02期

关键词：

TOLL-LIKE RECEPTORS; GENE-EXPRESSION; ZAP-70; EXPRESSION; GENOMIC ABERRATIONS; DISEASE PROGRESSION; ANTIGEN RECEPTOR; MUTATION STATUS; CROSS-LINKING; SURVIVAL; IGM;

D O I：

10.1182/blood-2010-05-284984

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-kappa B activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-kappa B activation, we detected phosphorylation of SYK and I kappa B alpha, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370. (Blood. 2011;117(2):563-574)

引用

页码：563 / 574

页数：12

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[1] Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling [J].