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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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) | 0,004 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».