Inhibition of Threonine Tyrosine Kinase Suppressed <i>TP53-</i>mutated Acute Myeloid Leukaemia Via Synergism with Venetoclax and Activation of the Cgas-Sting Pathway
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".