Pharmacological targeting of eIF4E in primary CLL lymphocytes

Eukaryotic translation initiation factor 4E (eIF4E) is a rate-limiting factor for cap-dependent protein synthesis regulated by the PI3K/AKT/mTOR signaling pathway as well as MNK1/2-mediated phosphorylation.1, 2 In addition to its cytoplasmic functions in translation, nuclear eIF4E aids in the cytoplasmic export of specific mRNAs.1, 3 eIF4E is overexpressed in many cancers and has been reported to have important roles in the development and progression of hematological malignancies in animal models.2 However, the role of eIF4E in drug resistance in primary human cancer cells is less well documented.4, 5, 6 In this study, we sought to assess the contribution of eIF4E to fludarabine (FLU) resistance in primary chronic lymphocytic leukemia (CLL) lymphocytes as this nucleoside analog is used as a first-line treatment for the disease.7 To this end, we used a panel of primary CLL samples from 26 affected patients (Supplementary Table). To interfere with eIF4E function, we used Ribavirin, a well-characterized antiviral drug that has also been shown to target eIF4E in a variety of systems, including patients with acute myeloid leukemia (AML).6, 8, 9 A clinically achievable concentration of Ribavirin (10 μM), which was not cytotoxic to primary CLL lymphocytes in culture, significantly sensitized 76% of the samples tested to FLU with the sensitization index (R) ranging from 1.25 to eightfold (Figures 1a, P