Apoptotic Blocks in Primary Non-Hodgkin B-Cell Lymphomas Identified By BH3 Profiling
Notice bibliographique
Résumé
Abstract Background: The anti-apoptotic protein BCL2 is expressed in most non-Hodgkin lymphomas (NHL) including chronic lymphocytic leukemias (CLL), mantle cell lymphomas (MCL), follicular lymphomas (FL), diffuse large B cell lymphomas (DLBCL) and marginal zone lymphomas (MZL). BCL2 expression is associated with an inferior survival when co-expressed with MYC, an oncogene that induces cellular proliferation, especially in high-grade lymphomas with translocations in MYC and BCL2(HGBL-DH). Venetoclax, a selective BCL2 inhibitor, is effective in CLL, but has modest clinical activity in other NHLs. CLL has been shown to be "primed" and BCL2-dependent, predicting for a favorable response to venetoclax using BH3 profiling. This technique measures mitochondrial outer membrane depolarization (MOMP) after exposure to synthetic pro-apoptotic BH3 peptides that have different affinities to anti-apoptotic proteins BCL2, BCLXL, MCL1 and BCLW. Cells with functional BAX/BAK undergo MOMP after exposure to pro-apoptotic proteins BIM/BID. "Primed" cells undergo MOMP after exposure to BIM, BID and PUMA, where the latter inhibits all anti-apoptotic proteins. Thus, inhibiting the anti-apoptotic proteins would initiate apoptosis. We hypothesized that BH3 profiling of NHLs could help us understand the mechanisms of venetoclax-resistance in BCL2+ NHL. This has not yet been performed due to the rarity of samples archived as a viable cell suspension. Methods: We performed BH3 profiling on 138 B-cell NHLs (36 CLL/SLL, 42 FL, 38 DLBCL, 10 HGBL-DH, 13 MCL, and 3 MZLs) and 34 controls (14 tonsils and 20 peripheral blood mononuclear cells). NHLs were taken prior to (n=107) or after therapy (n= 31). A T-test and ANOVA were performed to determine the differences in MOMP between NHLs subtypes and normal B cells. We also profiled HGBL-DH cell lines to determine if chemotherapy (cyclophosphamide, doxorubicin, vincristine, dexamethasone and bendamustine) could potentiate venetoclax-responses. We measured the levels of anti-apoptotic proteins and MYC by immunoblot, speculating that proteins with short half-lives (MYC and MCL1) may fall upon cell-cycle arrest. Results: Normal B and T lymphocytes were primed and depended on BCL2, MCL1 and BCL-XL. NHLs were primed in 85% (121/138) of cases, 5% (6/138) were unprimed (no PUMA response) and 10% (14/138) were incompetent to undergo MOMP (no BIM/BID response), indicating dysfunctional BAX/BAK. The latter apoptotic defect was mainly seen in DLBCL (10/14). CLL and HGBL-DH had significantly higher venetoclax responses than DLBCL, MCL and FL (all p <0.05). Responses to venetoclax were only observed in samples that expressed BCL2 protein. In BCL2+ NHLs, increased MOMP was achieved by combining venetoclax with the MCL1-specific inhibitor MS1. Inhibiting BCLXL or BCLW did not increase MOMP, suggesting that MCL1 inhibits apoptosis in the absence of BCL2. Profiling HGBL-DH cell lines OCI-Ly8 and Toledo after chemotherapy, only doxorubicin and vincristine increased priming (PUMA response), decreased the levels of MYC and MCL1 proteins and potentiated venetoclax-induced apoptosis (all p <0.05). Conclusion: CLL and HGBL-DH were the most BCL2-dependent NHLs and had the highest responses to venetoclax. Venetoclax-resistance in our NHLs was due to the presence of MCL1, the lack of BCL2 expression and dysfunctional BAX/BAK. In the former scenario, resistance may be overcome by combining venetoclax with vincristine and doxorubicin, two drugs used in standard RCHOP. Disclosures Johnson: Seattle Genetics: Honoraria; Merck: Consultancy, Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Steidl:Juno Therapeutics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding. Scott:Janssen: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Celgene: Consultancy, Honoraria; Roche: Research Funding. Letai:Flash Therapeutics: Equity Ownership; Vivid Biosciences: Equity Ownership; AbbVie: Consultancy, Other: Lab research report; Novartis: Consultancy, Other: Lab research report; AstraZeneca: Consultancy, Other: Lab research report.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».