What question did this study set out to answer?

This research aims to understand how TP53 mutations influence survival and adaptation in acute myelogenous leukemia (AML).

May 29, 2026

TP53 mutation adoption of stromal-adhesion/neuronal-like programs as a driver of stress adaptation and acute myelogenous leukemia cell survival.

Key Points

This research aims to understand how TP53 mutations influence survival and adaptation in acute myelogenous leukemia (AML).
Screened 311 AML patients, including 93 with NGS data (32 TP53-mutated, 61 wild type)
Analyzed overall survival using Kaplan–Meier and Cox regression
Utilized Random Forest and pathway enrichment analysis to identify transcriptional modules and pathways.
Overall survival was 168 days for TP53+ vs. 624 days for wild type (HR = 4.2, p = 0.02)
Identified significant upregulation of pathways related to stromal dependence and neurotrophin signaling (p = 0.0004 and p = 0.0006)
Noted downregulation of pathways relevant to cytokine interaction and myeloid differentiation (p = 4.7×10−4 and p = 1.2×10−3).

Abstract

6545 Background: TP53 -mutated AML is associated with early relapse and poor survival, highlighting the need to define p53-driven transcriptional programs that may reveal targetable therapeutic vulnerabilities. Systematic deconvolution of the TP53-associated transcriptome provides a critical framework to uncover dependencies associated with drug resistance. Methods: After IRB approval, 311 AML patients were screened; 93 (30%) with available NGS were included (32 TP53-mutated, 61 TP53-wild type). Bulk transcriptome data were available for 11 TP53+ and 13 TP53-WT cases. Overall survival was analyzed using Kaplan–Meier and multivariable Cox regression. Transcriptional modules predictive of TP53+ AML were identified using Random Forest and pathway enrichment via KEGG/Reactome with confirmation by ToppGene. Public single-cell RNA-seq datasets from the MIT Single Cell Portal were queried to assess whether low TP53 expression states recapitulate bulk TP53-mutated transcriptional programs. Results: OS was 168 and 624 days (d) in TP53+ and TP53 WT cases (HR = 4.2, p = 0.02). Only CK retained independent effect for OS (HR = 0.33, 95% CI = 0.13–0.82, p = 0.014) when accounting for TP53 mut status and age. TP53 mut status imprinted a deep transcriptomic signature (AUC = 0.94). Top upregulated genes included FHL2 (p = 4.0×10−6, FDR = 0.004), HMGA2 (p = 1.4×10−3, FDR = 0.02), ARHGEF12 (p = 5.2×10−3, FDR = 0.04), RYR3 (p = 2.1×10−3, FDR = 0.03), LRRC7 (p = 7.7×10−3, FDR = 0.05), ALDH1A1 (p = 1.4×10−3, FDR = 0.02). Top downregulated genes included CSF1 (p = 4.7×10−4, FDR = 0.007), CD34 (p = 1.2×10−3, FDR = 0.01). To uncover pathway-level shifts co-opted by TP53+ AML, we contrasted pathway-level projection against TP53 WT cases. Upregulated pathways included adhesion / stromal dependence (p = 0.0004; FDR = 0.0028), neurotrophin / calcium signaling / Ca2+-coupled survival (p = 0.0006, FDR = 0.0021). However, downregulated pathways included cytokine-cytokine receptor interaction (p = 4.7×10−4, FDR = 0.007) and myeloid differentiation (p = 1.2×10−3, FDR = 0.01) Fig. 2. Interestingly, in lineage-resolved single-cell reference, low TP53 GE was visually colocalized with perivascular/stromal cells exhibiting high FHL2 and THY1 (CD90) expression. This data reconfirms prior data suggesting that reduced TP53 function favors niche-adapted perivascular/MSC-like reprogramming (THY1-high) that protects “resistant AML clones” (Mizuno et al., ASH 2024). Conclusions: These findings unveil that TP53+ AML co-opts leukemic blasts toward a stromal-adhesive and neuronal-like state, allowing survival under metabolic and therapeutic stress. Reversing stromal adhesive / neuronal-like rewiring may attenuate TP53 + blasts hijacking on vascular niche that maintains relapse potential.

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