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The mithralog EC-7072 is highly cytotoxic to chronic lymphocytic leukemia cells by targeting the B-cell receptor signaling pathway

ABSTRACT: EC-7072, an analogue of Mithramycin A, exerts a direct cytotoxic effect on primary leukemic cells from patients with chronic lymphocytic leukemia (CLL) in vitro. To elucidate the underlying mechanisms mediating this effect, RNA sequencing was carried out employing total RNA from primary leukemic cells exposed to EC-7072. Data analysis revealed a dramatic impact of the compound on the transcriptional profile of CLL cells, unraveling a modulation of key mediators associated to homeostasis and survival of CLL cells, including B-cell receptor signaling. Likewise, EC-7072 activated the expression of a pro-apoptotic network, while downregulating the expression of essential anti-apoptotic proteins such as BCL2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123777 | GEO | 2019/10/01

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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The mithralog EC-7072 is highly cytotoxic to chronic lymphocytic leukemia cells by targeting the B-cell receptor signaling pathway

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