Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2

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BlankInflammatory cytokines and signaling pathways are associated with survival

of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2.

A Schulz, G Toedt, T Zenz, S Stilgenbauer, P Lichter, and M Seiffert

Haematologica, December 6, 2010; .

Germany;

Background. Chronic lymphocytic leukemia cells show prolonged survival in vivo,

but rapidly die by spontaneous apoptosis in vitro, unless they are cocultured

with stromal cells or non-malignant leukocytes. The objective of this study was

a characterization of the survival-inducing cross-talk of chronic lymphocytic

leukemia cells with their microenvironment to identify novel therapeutical

targets. Design and Methods. Therefore, we analyzed and compared

microarray-based expression profiles of chronic lymphocytic leukemia cells

before and after three different survival-inducing culture conditions: (i)

stromal cell coculture, (ii) stromal cell conditioned medium and (iii) high cell

density cultures of unsorted peripheral blood mononuclear cells. To study the

composition of soluble factors present in these cultures, cytokine antibody

arrays were applied. Results. The different survival-supportive culture

conditions induced distinct gene expression changes, the majority of which were

common to all three conditions. Pathway analyses identified - in addition to

known signaling networks in chronic lymphocytic leukemia - novel pathways, of

which Toll-like receptor signaling, nuclear respiratory factor-2 (NRF2) mediated

oxidative stress response, and signaling via triggering receptor expressed on

myeloid cells-1 (TREM1) were the most relevant. A high proportion of

up-regulated genes were inflammatory cytokines, of which chemokine (C-C motif)

ligand 2 (CCL2) was shown to be induced in monocytes by the presence of chronic

lymphocytic leukemia cells in vitro. In addition, increased serum levels of this

chemokine were detected in chronic lymphocytic leukemia patients. Conclusions.

In summary, our data present several lines of evidence that an inflammatory

microenvironment is induced in survival-supportive cultures of chronic

lymphocytic leukemia cells which might be directly or indirectly involved in the

prolonged survival of the malignant cells.

PMID: 21134984