Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro, and present at abnormally high levels in vivo

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BlankBlood First Edition Paper, prepublished online July 26, 2010; DOI

10.1182/blood-2010-05-284505.

Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic

leukemia cells, which is induced by CLL cells in vitro, and present at

abnormally high levels in vivo

a Seiffert1, Schulz1, Sibylle Ohl1, Hartmut Döhner2, Stephan

Stilgenbauer2 and Lichter1,*

1 German Cancer Research Center, Dept. for Molecular Genetics, Heidelberg,

Germany; 2 Innere Medizin III, Universitaet Ulm, Ulm, Germany

* Corresponding author; email: peter.lichter@...

Abstract

Accumulation of leukemic cells in patients with chronic lymphocytic leukemia

(CLL) is due to prolonged cell survival, rather than increased proliferation.

Survival of CLL cells depends on microenvironmental factors. Even though

long-lived in vivo, CLL cells rapidly die by spontaneous apoptosis in vitro,

unless cocultured with stromal cells or their conditioned medium. In the present

study, we show that survival of CLL cells is maintained in high cell density

cultures, where the main pro-survival activity is delivered by monocytes.

Cytokine array and ELISA studies revealed increased expression of soluble CD14

by monocytes in the presence of CLL cells. The addition of recombinant soluble

CD14 to primary CLL cells resulted in significantly increased cell survival

rates, which were associated with higher activity of the transcription factor

NF(kappa)B. Quantification of serum levels of soluble CD14 revealed abnormally

high levels of this protein in CLL patients, indicating a potential role of

soluble CD14 in vivo. In summary, the presented data show that monocytes help in

the survival of CLL cells by secreting soluble CD14, which induces NF(kappa)B

activation in these cells, and that CLL cells actively shape their

microenvironment by inducing CD14 secretion in accessory monocytes.