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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BlankHaematologica 2010, 10.3324/haematol.2010.031377

Inflammatory cytokines and signaling pathways are associated with survival of

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

Schulz1, Grischa Toedt1, Thorsten Zenz2, Stephan Stilgenbauer2,

Lichter1,*, a Seiffert1

1 German Cancer Research Center, Germany;

2 University of Ulm, Internal Medicine III, Germany

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

ABSTRACT

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.