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To compare gene signature of CLL cells from patients with high versus low lymphocyte counts

ABSTRACT: In chronic lymphocytic leukemia (CLL) the increment in peripheral blood lymphocytes is slower than the expected increment calculated from the cells’ proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase3, higher cleaved poly (ADP-ribose) polymerase (PARP) levels (P <0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that signal transducer and activator of transcription 3 (STAT3) protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 in MM-1 cells did not protect the cells. Rather, it upregulated caspase3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase3 promoter and a luciferase assay, chromatin immunoprecipitation (ChIP), and an electromobility shift assay (EMSA) revealed that STAT3 activated caspase3. However, caspase3 levels increased only when STAT3 levels were sufficiently high. Using ChIP and EMSA, we found that STAT3 binds with low affinity to the caspase3 promoter, suggesting that at high levels, STAT3 activates a negative proapoptotic feedback mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68721 | GEO | 2015/05/12

SECONDARY ACCESSION(S): PRJNA283501

REPOSITORIES: GEO

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Project description:Chronic lymphocytic leukemic B cells (CLL) reside in close contact with activated endothelial cells (EC) in infiltrated tissues. Here, we investigated the interactions between EC and CLL cells, highlighting molecular networks involved in this cellular crosstalk. We co-cultured purified CLL cells on HUVEC monolayer (HC) or in medium alone. We found that EC protected CLL from spontaneous apoptosis. A 2.2-fold increase in relative viability in IGHV mutated CLL and a 6.1-fold increase in IGHV unmutated CLL was detected in co-culture. Moreover, the endothelial cell layer decreased the in vitro sensitivity of CLL cells to Fludarabine-induced apoptosis. Physical contact with EC is essential for protection to apoptosis. The insertion of a microporous membrane or blocking adhesion with anti-CD106 and anti-CD18 antibodies determined the complete abrogation of apoptosis protection. On the other hand, a reduction of apoptosis was measured in CLL cells cultured with conditioned medium collected from HC, implying that survival is partially mediated by soluble factors. Overall 1944 genes were modulated in CLL by co-culture. The EC contact seem to determine on CLL a kind of microenvironmental-driven angiogenic switch, improve the secretion of cytokines regulating tissue elements such as stromal cells and macrophages and also increase anti-apoptotic molecules. Our study support the line of evidence indicating endothelial cells as a major player in the CLL-infiltrated microenvironments are able to create a vicious cycle of cooperation that strongly sustains leukemic cell survival, protects CLL from drug-induced apoptosis and widely modifies CLL phenotype. Large-scale gene expression profiling (GEP) was performed on total RNA extracted from purified CD19+ cells isolated from 9 individual CLL patients which were separated in 3 experimental subsets: (i) freshly isolated cells (CLL baseline), (ii) CLL cells cultured in medium alone for 48 hours (CLL only) and (iii) CLL cells co-cultured 48h on HUVEC layer (CLL HC).

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To compare gene signature of CLL cells from patients with high versus low lymphocyte counts

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