Pharmacological targeting of eIF4E in primary CLL lymphocytes
Notice bibliographique
Résumé
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).
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».