Pharmacological targeting of eIF4E in primary CLL lymphocytes

VERONICA MARTINEZ MARIGNAC; MAY SHAWI; EDGAR PINEDO CARPIO; LAWRENCE PANASCI; WILSON PANASCI; FILIPPA PETERSON; RAQUEL ALOYZ

Montreal

Jornada; Proceedings of the McGill-CIHR DDTP Research Retreat 2013; 2013

Mc Gikk University

The eukaryotic translation initiation factor 4E (eIF4E) is over-expressed in many cancers, including hematological malignancies, and has been reported to play important roles in development, progression, as well as chemoresistance of cancer. We report for the first time that eIF4E is highly expressed and variably phosphorylated in primary chronic lymphocytic leukemia (CLL) lymphocytes. Furthermore, in these leukemic cells, two inhibitors of eIF4E functions, Ribavirin and the MNK inhibitor CGP57380, decreased drug resistance ex vivo. Ribavirin sensitization to fludarabine (FLU) preferentially occurred in samples with unmutated IgVH and high TCL-1 expression, both associated with bad prognosis in CLL. CGP5738 sensitized only unmutated CLL lymphocytes, which we show express higher basal levels of phosphorylated eIF4E . We found that Ribavirin can abrogate FLU-induced changes to eIF4E cellular localization and reduce homeostatic pro-survival signals induced by FLU. Importantly, when CLL lymphocytes are co-cultured with stromal cells, which stimulate pro-survival signals, eIF4E targeting can decrease these micro-environmental clues and cause cell death. Biologically, our results underscore the contribution of eIF4E to the survival of quiescent primary human malignant cells.