P471: POLO-LIKE KINASE 4 INHIBITION INDUCED ANTI-LEUKAEMIC EFFECTS THROUGH HISTONE MODIFICATION IN TP53 MUTATED ACUTE MYELOID LEUKAEMIA
Notice bibliographique
Résumé
Background: Current treatment for acute myeloid leukaemia (AML) entails intensive chemotherapy and allogeneic hematopoietic cell transplantation. However, these approaches have not been effective in patients with TP53 mutated AML and their 5-year overall survival was less than 10%. In silico analysis showed that Polo-like kinase 4 (PLK4) was among the 45 functional and druggable genes that were preferentially expressed in this AML subtype. We reported therein the therapeutic mechanisms of PLK4 inhibition and its hitherto undescribed effects on epigenetic regulation of leukaemogenesis. Aims: To understand the therapeutic effects and mechanisms of PLK4 inhibition in AML. Methods: PLK4 inhibition or gene knockout has been shown to suppress leukaemia growth in TP53 mutated AML both in vitro and in vivo. To examine the therapeutic mechanisms, transcriptome analyses were performed and differentially expressed genes (DEGs) induced by PLK4 inhibitor CFI-400945 were examined in TP53 mutated AML cell line (KO52). To circumvent the confounding effects of PLK4 inhibition on ploidy, leukemia cells were purified based on the ploidy status (2N and 4N) before RNA-Seq. Molecular and cellular effects of CFI-400945 were subsequently investigated. Results: A total of 937 and 564 DEGs were identified when 2N and 4N cells in CFI-400945 treated cells and vehicle controls were compared. Gene set enrichment analysis (GSEA) showed that genes associated with histone methylation, including H3K27me3 and polycomb repressive complex 2 (PRC2 complex), were negatively enriched upon CFI-400945 treatment. A comparison of our transcriptome data with public datasets (GSE142764 and GSE132407) showed that the DEGs upon PLK4 inhibition were significantly correlated with those genes perturbed by protein arginine methyltransferase 5 (PRMT5) inhibition. CFI-400945 increased global H3K27me3 expression in both 2N and 4N populations. PLK4 was found to bind with PRMT5 as shown by co-immunoprecipitation and its inhibition significantly suppressed PRMT5 phosphorylation. PRMT5 inhibition induced global increases in O-GlcNAcylation and protein expression of EZH2, a subunit of PRC2, and the responses were reduced by O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) inhibitor (OGTi). To examine the relevance of histone modification in gene expression in AML, we selected a panel of genes that possessed H3K27me3 mark in their promoters and were reported to play key roles in leukemogenesis including leukemic stem cell signature, apoptosis, DNA damage, cellular proliferation, and immune surveillance, for further examination. Inhibition of OGT and PRC2 by OGTi and A395/EED226 ameliorated the downregulation of these genes caused by CFI-400945. H3K27me3 chromatin immunoprecipitation (ChIP) PCR targeting their promoter regions showed that PLK4 inhibition induced increase in H3K27me3 enrichment, which was also ameliorated by PRC2 or OGT inhibition. Furthermore, increased DNA damage, apoptosis induction and proliferation suppression upon PLK4 or PRMT5 inhibition were ameliorated by PRC2 inhibitor. Summary/Conclusion: The observations supported a novel PLK4/PRMT5/EZH2/H3K27me3 axis that might account for the anti-leukemic effects of PLK4 inhibition on TP53 mutated AML. Acknowledgements: This research was supported by Health@InnoHK, Innovation and Technology Commission of the HKSAR, Theme-based Research Scheme (T12-702/20-N), HMRF (08191906), Li Shu Fan Medical Foundation, Ying Wan Leung Research Fund and Collaborative Research Fund (C7028-19G), and Tang King Ying Research Fund. Keywords: Acute myeloid leukemia, TP53, Epigenetic
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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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,003 |
| 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,002 |
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 ».