Abstract PR09: APOBEC3A sensitizes leukemia cells to inhibitors of the replication checkpoint
Notice bibliographique
Résumé
Abstract The human APOBEC3 family of DNA-cytosine deaminases comprises seven members (A3A-A3H) that act on single-stranded DNA (ssDNA). The APOBEC3 enzymes are best defined by their capacity to restrict viral infection, however several family members are also capable of causing cellular DNA damage that leads to activation of DNA damage responses. Mutational signatures consistent with APOBEC3 activity have been identified in cancer genomes, and elevated expression of APOBEC3 enzymes has been observed in solid tumors. These findings point to a role for APOBEC3 enzymes in cancer-associated mutagenesis, however the impact of APOBEC3 activity within cancer cells has not been examined to date. We hypothesized that A3A is a potential source of mutagenesis in leukemia, since it is endogenously expressed at high levels in hematopoietic cells. To identify hematologic malignancies in which A3A expression is elevated, we examined RNA sequencing from adult and pediatric leukemias in the TCGA and TARGET databases. We found elevated A3A expression in a subset of pediatric and adult acute myeloid leukemia (AML). Additionally, we found that high A3A expression was associated with decreased survival, suggesting that new therapeutic options are important for patients with this type of malignancy. Since we have previously demonstrated that A3A acts on the cellular genome during replication, we hypothesized that abrogation of the replication checkpoint will produce genotoxicity and cell death in leukemias with elevated A3A expression. We therefore investigated the DNA damage response to A3A activity in leukemia cells by generating cell lines with inducible A3A expression. We found increased Ataxia Telangiectasia and Rad3-Related (ATR)-mediated phosphorylation of Chk1 (at serine 317 and serine 345) by Western blotting, and G2 arrest by flow cytometry. These results demonstrate that A3A causes replication checkpoint activation in leukemia cell lines. We investigated the potential for selective targeting of A3A-expressing AML cells by inhibition of replication checkpoint kinases. We found that A3A expression sensitized THP1 cells to ATR kinase inhibition, resulting in decreased viability, apoptosis, and abrogation of cell cycle arrest. We also found that Chk1 inhibition combined with A3A expression results in synthetic lethality in these cells. We determined that synthetic lethality with A3A is specific to the inhibition of ATR-Chk1 pathway and does not occur after inhibition of Ataxia Telangiectasia Mutated (ATM). We propose that A3A acts on ssDNA during replication in leukemia cells. ATR-Chk1 signaling is required for genome protection when A3A is active, and inhibition of this checkpoint results in cytotoxicity. These data reveal a new vulnerability of AML cells with elevated A3A expression and suggest that A3A is a biomarker for treatment with ATR kinase inhibitors. This abstract is also being presented as Poster B18. Citation Format: Abby M. Green, Konstantin Budagyan, Katharina E. Hayer, Matthew D. Weitzman. APOBEC3A sensitizes leukemia cells to inhibitors of the replication checkpoint [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR09.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 ».