Abstract 210: Targeting the mitochondrial DNA polymerase gamma with 2’3’-dideoxycytidine as a novel therapeutic strategy for acute myeloid leukemia
Notice bibliographique
Résumé
Abstract A subset of AML cells display unique mitochondrial characteristics such as increased mitochondrial DNA (mtDNA), mt mass, and sensitivity to inhibition of mtDNA transcription and protein translation. Given these unique mitochondrial characteristics, we evaluated the effect of inhibiting mtDNA replication by targeting the mtDNA polymerase gamma (POLG). POLG is a nuclear-encoded gene that replicates and repairs mtDNA. POLG mRNA is increased in leukemia cell lines and a subset of AML patients. We evaluated the preclinical efficacy of targeting POLG using the nucleoside analog 2’,3’-dideoxycytidine (ddC), an FDA-approved anti-retroviral drug that cross-reacts with POLG. Treatment with ddC at 500nM depleted mtDNA by >90%, decreased mtDNA-encoded COXI and COXII proteins and basal oxygen consumption, and induced apoptosis in AML cell lines (OCI-AML2, TEX, K562). ddC further decreased cell viability in a subset of primary AML cells, while normal peripheral blood stem cells (PBSC’s) were resistant to ddC in vitro. Next, we assessed the preclinical efficacy and toxicity of ddC in an OCI-AML2 xenograft model of human AML. Treatment with 35mg/kg of i.p. ddC induced tumor regression and decreased tumor mass by >75% compared to vehicle. No toxicity was observed including changes in liver enzymes or organ histology. We also observed reductions in COXI and COXII protein in tumors but not liver excised from treated mice. We next investigated the mechanism for preferential sensitivity to ddC in AML cells. A two-fold greater decrease in mtDNA content was observed in AML cells treated with ddC compared to PBSC’s, in part explaining the heightened sensitivity. However, the increased sensitivity to ddC in AML was not due to increased mtDNA turnover as mtDNA depletion after ethidium bromide treatment was comparable between AML and PBSC’s. Therefore, we investigated the role of ddC uptake and metabolism. ddC is transported by nucleoside transporters (ENT’s, CNT’s) and activated by cytoplasmic nucleoside kinases to ddC-triphosphate (ddC-TP). Analysis of Haferlach et. al. (2010) dataset demonstrated that a subset of AML cells have higher mRNA expression of hENT2 and hCNT1, and the nucleoside diphosphate kinases NME1,2,3,5 compared to normal hematopoietic cells. Using mass spectrometry, we observed higher levels of ddC and ddCTP in sensitive AML cells compared to resistant cells. Lastly, knockdown of the deoxycytidine kinase rescued ddC cytotoxicity in TEX cells. In summary, targeting POLG with ddC displays anti-leukemic activity in both in vitro and in vivo models of AML. The preferential toxicity of ddC is due, in part, to increased rates of uptake and activation in AML along as well as their increased sensitivity to inhibition of oxidative phosphorylation. Thus, POLG inhibitors such as ddC may have clinical utility in a subset of AML. Citation Format: Sanduni Liyanage, Rose Hurren, Xiaoming Wang, Neil Maclean, Rebecca Laposa, Aaron Schimmer. Targeting the mitochondrial DNA polymerase gamma with 2’3’-dideoxycytidine as a novel therapeutic strategy for acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 210.
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) | 0,001 | 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 ».