Abstract 5538: Development of HDACi resistance in DLBCL leads to a switch in subtype towards a more differentiated B-cell and is associated with increased sensitivity to proteasome inhibition
Notice bibliographique
Résumé
Abstract Diffuse Large B Cell Lymhoma (DLBCL) is a highly heterogeneous disease in terms of clinical presentation, cell morphology, molecular characteristics and response to therapy. Gene expression profiling studies in patients have indicated that DLBCL can be sub-classified in relationship to the different stages of normal B cell development at which the cancer arises; germinal center B cell (GCB) and activated B cell (ABC). More recently, a similar approach distinguished three different reproducible clusters referred to as oxidative phosphorylation (OxPhos), B cell receptor/proliferation (BCR) and host response (HR). Importantly, DLBCL has also been well characterized at the genomic level. A large number of genes encoding epigenetic modifying enzymes are mutated in DLBCL, which implicates epigenetic regulation as an important factor in DLBCL pathogenesis, and a potential target for therapy. Among epigenetic therapies, histone deacetylase inhibitors (HDACi) have shown some clinical activity in DLBCL patients ranging from 5 to 25%, although responsive patients ultimately develop resistance. Aiming to understand resistance and response to HDACi in DLBCL, we developed HDACi-resistant cell lines from the GCB and BCR subtype cells SUDHL6 and SUDHL4. Gene expression array analysis was performed in parental SUDHL6 and the resistant clone SUDHL6-X. Strikingly, we found that the resistant cells have switched gene expression profile from GCB to ABC subtype and from BCR to OXPHOS. Also, we observe features of more differentiated, plasmablast-like cells in SUDHL6-X cells and in all other resistant subclones we developed, including inactivated B cell receptor signaling, increased endoplasmic reticulum stress and activation of the unfolded protein response. These characteristics are reflected in a distinctive response pattern to other targeted drugs. We observe that HDACi-resistant cells become cross-resistant to the anti-CD20 antibody rituximab, but, interestingly, they gain susceptibility to inhibitors of the proteasome bortezomib and MLN2238. Importantly, analysis of lymphoma cells isolated from de novo resistant DLBCL patients treated with the HDACi panobinostat for 15 days showed a switch in gene expression profiles from GCB to ABC, similar to SUDHL6X cells, indicating that our observations are not exclusive of in vitro systems. In conclusion, we have shown for the first time that resistance to HDACi is associated with differentiation of lymphoma cells that we predict makes them insensitive to drugs targeting the B cell receptor and anti-CD20 antibody, but sensitive to proteasome inhibition. Citation Format: Daphné Dupéré-Richer, Mena Kinal, Filippa Pettersson, Mona Hassawi, Yang ShaoNing, Torsten H. Nielsen, Kathleen Klein, Teresa Ezponda-Itoiz, Jonathan D. Licht, Nathalie Johnson, Sarit E. Assouline, Leandro Cerchietti, Wilson H. Miller, Koren K. Mann. Development of HDACi resistance in DLBCL leads to a switch in subtype towards a more differentiated B-cell and is associated with increased sensitivity to proteasome inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5538. doi:10.1158/1538-7445.AM2014-5538
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) | 0,000 | 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) | 0,004 | 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 ».