Pharmacological targeting of eIF4E in primary CLL lymphocytes
Bibliographic record
Abstract
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 μ M ), 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 <0.001 and Supplementary Table ). Sensitization was observed in 50% of the CD38-positive samples, 60% of the del17-positive samples, 50% of the del11-positive samples and samples from clinically resistant patients ( Supplementary Table ). Notably, the effect of Ribavirin was significantly associated with IgVH status, as revealed by the non-parametric Spearman Rank Order Correlation ( r =−0.45, P =0.02); that is, better sensitization in high-risk U-IgVH samples, ( Figure 1b ). Figure 1 The alternative text for this image may have been generated using AI. Full size image Ribavirin sensitization to FLU is associated with IgVH mutational status and abrogation of FLU-induced AKT phosphorylation and BCL2 expression in vitro . ( a ) The open circles represent the R -value calculated as the ratio between (FLU IC 50 )/(IC 50 of FLU+Ribavirin (Rib) and vehicle (CTL) in each sample tested. The close circles represent the median values (±s.e.) (* P <0.001, Mann–Whitney U -statistic). ( b ) Graphical representation of the percentage of mutations at the IgVH locus ( y axis) and Ribavirin-mediated sensitization to FLU ( R -values, x axis). The horizontal line on the y axis (2%) indicates the cutoff used to define IgVH status. ( c ) The expression and phosphorylation of the indicated targets was assessed by western blot analysis in two representative samples 12 h after ex vivo treatment with vehicle, the FLU IC 50 concentration of each sample in combination with vehicle or with 10 μ M Ribavirin. Sensitized: R =5; not sensitized: R =1. ( d ) The y axis represents the changes in AKT phosphorylation (S473) with respect to vehicle (CTL)-treated lymphocytes 12 h after the treatment as indicated ( x axis). The bars represent the median values and the 25th/75th percentile intervals ( n =7). The Krustal–Wallis analysis of variance (*** P <0.001) followed by paired t -test (** P =0.014 and * P =0.035). A representative sample showing AKT phosphorylation (S473) after treatment with vehicle (black line), FLU alone (IC 50 concentration, red line) or in combination with 10 μ M Ribavirin (FLU+Rib; green line). The gray area represents the negative control (control isotype antibody).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".