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

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BlankBlood, 13 January 2011, Vol. 117, No. 2, pp. 563-574.

Prepublished online as a Blood First Edition Paper on October 12, 2010; DOI

10.1182/blood-2010-05-284984.

The lymph node microenvironment promotes B-cell receptor signaling, NF-(kappa)

B activation, and tumor proliferation in chronic lymphocytic leukemia

Yair Herishanu1, Pérez-Galán1, Delong Liu2, Angélique Biancotto3,

Stefania Pittaluga4, Berengere Vire1, Federica Gibellini1, Ndegwa Njuguna1,

Elinor Lee1, Lawrence Stennett1, Nalini Raghavachari5, Poching Liu5, J. Philip

McCoy3, Mark Raffeld4, alice Stetler-son4, Constance Yuan4,

Sherry6, Diane C. Arthur4, Irina Maric7, Therese White8, Gerald E. Marti9,

Munson2, Wyndham H. 9, and Wiestner1

1 Hematology Branch, National Heart, Lung and Blood Institute (NHLBI), National

Institutes of Health (NIH), Bethesda, MD; 2 Mathematical and Statistical

Computing Laboratory, Division of Computational Biosciences, Center for

Information Technology, NIH, Bethesda, MD; 3 Center for Human Immunology, NIH,

Bethesda, MD; 4 Laboratory of Pathology, National Cancer Institute (NCI),

Bethesda, MD; 5 Bioinformatics Core, NHLBI, NIH, Bethesda, MD; 6 Surgery Branch,

NCI, Bethesda, MD; 7 Department of Laboratory Medicine, Clinical Center, NIH,

Bethesda, MD; 8 Center for Cancer Research, NCI, Bethesda, MD; and 9 Center for

Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, MD

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, (kappa) B

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 .