Inhibition of Threonine Tyrosine Kinase Suppressed <i>TP53-</i>mutated Acute Myeloid Leukaemia Via Synergism with Venetoclax and Activation of the Cgas-Sting Pathway
Notice bibliographique
Résumé
Background. Acute myeloid leukaemia (AML) carrying TP53 mutation portends an extremely poor prognosis. Intensive chemotherapy and allogeneic haematopoietic stem cell transplantation are largely ineffective and the 5-year overall survival was less than 10%. There is an unmet need for novel therapeutic strategies. Methods. Vulnerabilities of TP53-mutated AML were examined via in silico analyses of public databases. Potential targets were validated using AML derived cell lines, isogenic cell models and primary AML samples. In vitro assays for cell viability, apoptosis, senescence, DNA damage and immune activation were performed. Results. Examination of the BeatAML, Leucegene and DepMAP databases identified threonine tyrosine kinase (TTK), a key component of the spindle assembly checkpoint (SAC), among a total of 45 highly expressed and functionally essential genes in TP53-mutated AML. Upregulation of TTK by TP53 mutation was confirmed in an isogenic MV4-11 cell line model with TP53 mutant knock-in. In vitro treatment of TP53-mutated AML cell lines with TTK inhibitors CFI-402257, AZ3146 and BAY1217389, or specific TTK knock-down significantly reduced cell viability. CFI-402257 induced apoptosis in TP53-mutated AML, as shown by the increases in annexin V and cleaved caspases. It also induced increase in mitotic defects, aneuploidy, micronuclei formation and DNA damage in this AML subtype. As micronuclei has been shown to activate the cGAS-STING pathway, the latter was further examined. Co-localization of cGAS with micronuclei inducible by CFI-402257 was readily identified. There was significant increase in STING dimerization, and downstream factors including increased NF-κB and IRF3 phosphorylation, consistent with the activation of cGAS-STING pathway. CFI-402257 also triggered senescence-like phenotype, with increase in SA-β-galactosidase staining and decrease in lamin B1 expression. Expression of senescence-associated secretory phenotype (SASP) and inflammatory cytokines including TNFa, IL6, CXCL10, CCL2 and CXCL8 were significantly increased. Phagocytic activity of THP-1 derived macrophages was increased upon co-culture with TP53-mutated AML cells in the presence of CFI-402257, suggesting activation of innate immune response. To identify therapeutic partners that show synergism with CFI-402257 in TP53-mutated AML, we performed a combination drug screen of 55 FDA-approved anti-cancer drugs in TP53-mutated AML cell lines, in the presence of CFI-402257. Venetoclax was among the most synergistic partners with CFI-402257 in suppressing leukaemia growth and inducing apoptosis. In vivo effects of the combination treatment and the therapeutic mechanisms are being examined. Conclusion. TTK inhibition effectively suppressed leukaemia growth in TP53-mutated AML cells via DNA damage and activation of cGAS-STING pathway. There was demonstrable synergism with venetoclax. Our results have provided important leads for further mechanistic and clinical studies.
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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) | 0,001 | 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 ».