Abstract 2284: Dissecting signaling networks involved in the tumor-microenvironment crosstalk in chronic lymphocytic leukemia (CLL)

Abstract

Crosstalk between tumor cells and the microenvironment is often a prerequisite for carcinogenesis. CLL, the most common leukemia in the western world, is an excellent model system to investigate this microenvironmental crosstalk. The dependence of the CLL cells for pro-survival support from the microenvironment is apparent from the induction of rapid spontaneous apoptosis in CLL cells in vitro unless they are cultured on feeder cells or treated with microenvironmental cytokines. CLL cells are also capable of inducing other non-malignant microenvironmental cells to form a pro-survival niche.We have used a tripartite strategy to characterize the interaction between CLL cells and their microenvironment. Firstly, we have quantified the interaction of pro-survival ligand-receptor pairs and their dose-response curves in primary CLL cells and non-malignant B cells. Of the ligand-receptor pairs tested, IL4 and CD40L were found to rescue primary CLL cells most effectively from apoptosis. The effector dependence of IL4 and CD40L displayed different saturation curves in CLL versus non-malignant B cells, pointing towards distinct differences in ligand-receptor interactions. Secondly, we have used a systems biology approach to identify central nodes in the survival network induced by the microenvironment. The model is generated from the kinetics of the transcriptome acquired from gene expression profiling CLL cells after microenvironmental stimulation. Via a procedure that involves gene-ranking, significance filtering and kinetic classification, deregulated genes have been identified. Model construction using these genes will yield central nodes which will be functionally validated on a cohort of patients. As a third approach, the pro-survival niche inducing property of CLL cells on other microenvironmental cells is studied by gene expression profiling differentiated monocytes, which arise when monocytes are cocultured with CLL cells (which support CLL survival) versus the differentiated monocytes which arise when cultured with non-malignant B cells. Analysis of the gene expression profiles revealed genes specifically deregulated due to the effect of CLL cells.This study will give us a deep insight into the signaling networks operating between the tumor and its microenvironment. This is certainly important for the identification of drug targets which can abrogate this interaction and thereby reduce the viability of the CLL cells in vivo.Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2284.