Abstract IA018: Vulnerabilities of TP53-mutated AML and therapeutic implications
Bibliographic record
Abstract
Abstract Acute myeloid leukemia (AML) is a complex and genetically diverse with an overall survival rate of less than 32%. Despite the remarkable success of targeted therapy in mediating remission, the emergence of acquired resistance remains a major clinical challenge to overcome. The prevailing understanding of acquired resistance identifies successive genetic changes as the primary cause.TP53 mutations are found in 70-80% of acute myeloid leukemia (AML) patients with complex karyotypes and associated with resistance towards both conventional chemotherapy and newly approved venetoclax plus azacytidine (VEN/AZA) combination. By using CRISPR-Cas9-edited isogenic AML cells harboring, mutation (6 missense mutations) or deletion (KO) of TP53, we found that TP53 mutant/KO cells are less sensitive to etoposide or VEN-AZA induced apoptosis compared to WT without defect in G1 arrest. Surprisingly, we found that TP53-mutant and TP53-wild-type (WT) isogenic AML cells and primary tumors (n=40) had comparable mitochondrial outer membrane permeabilization (MOMP) at baseline, despite the key role of TP53 in transcriptionally activating proapoptotic regulators of MOMP (such as BAX, PUMA, and NOXA). Based on these findings, we hypothesize that the targets downstream of mitochondrial permeabilization drive resistance to HMA/VEN combinations in TP53 mutant disease. By leveraging unbiased bulk RNA-seq and proteomics, and whole genome CRISPR-cas9 screen we identified IAPs as functional vulnerability. Collectively we reveal novel chemoresistance mechanisms in TP53 mutant/KO downstream of MOMP and provide a targeting strategy to improve existing therapy by targeting non-transcriptional function of TP53 in overcoming therapy resistance. Citation Format: Shruti Bhatt. Vulnerabilities of TP53-mutated AML and therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA018.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".