TP53 and PPM1D mutations in AML: Distinct frequencies, shared pathway, and adverse prognostic trends

Abstract

Abstract Background TP53 mutations (TP53-mt) are strongly associated with poor outcomes in acute myeloid leukemia (AML). PPM1D is a serine/threonine phosphatase that functions as a negative regulator of the p53 tumor suppressor pathway by dephosphorylating p53 and attenuating its activity. Somatic mutations in PPM1D are mostly gain-of-function and lead to an increase in phosphatase activity, which disables the p53-mediated DNA damage checkpoint, potentially leading to adverse clinical outcomes similar to those seen with TP53-mt. The impact of PPM1D on AML outcomes remains underexplored. Therefore, we sought to investigate the prognostic significance of TP53 and PPM1D mutations (PPM1D-mt) in a large, real-world AML cohort. Methods We conducted a single-center retrospective study of adult AML patients (2015–2023) to assess the impact of TP53-mt and PPM1D-mt on first-line treatment response, overall survival (OS), and event-free survival (EFS). Cytogenetic abnormalities were identified by karyotyping, and mutations were detected using next-generation sequencing (NGS). We collected baseline data on age, sex, ethnicity, comorbidities, AML subtype, cytogenetics per 2022 European LeukemiaNet, mutations, treatments, responses, and follow-up. Primary endpoints were composite complete remission (CCR) (complete response (CR) + complete response with incomplete count recovery (CRi)), OS, and EFS. Survival was estimated by Kaplan–Meier and compared by log-rank test. Multivariable logistic and Cox proportional hazards analysis adjusted for confounders. Results A total of 971 AML patients were treated at our center during the study period. The median age was 66 years (IQR 56–75); 55% were male, and 89% were White. 277 (29%) had high-risk cytogenetics. Average bone marrow blasts at diagnosis were 46%. Average absolute neutrophil count at diagnosis was 1.1 K/microL. TP53-mt occurred in 120 patients out of 629 who had NGS at baseline (19%) and PPM1D-mt in 10 out of 390 who underwent NGS at baseline (2.6%). Chromosome 17 abnormalities were seen in 93 patients (10%), and complex karyotype was seen in 212 patients (23%). Median follow-up was 41 months (range: 0.49–193.3). Among TP53-mt patients (n=120), 110 (92%) had high-risk cytogenetics. TP53-mt patients had lower odds of CCR (OR = 0.48; 95% CI: 0.26–0.88) compared to TP53-wildtype (wt). Compared to TP53-wt, TP53-mt had worse OS; the median OS was 5.6 vs. 15 months, and the 12-mo OS was 24% (95% CI 17- 33) vs. 55% (95% CI 51- 60) (log-rank P<0.05). TP53-mt was associated with higher mortality (HR = 1.64; 95% CI: 1.22–2.21) and shorter EFS (HR = 1.54; 95% CI: 1.15–2.06). Among PPM1D-mt patients (n=10), 6 (60%) had high-risk cytogenetics and 5 (50%) had co-occurring TP53-mt. The average white blood cell counts (2 vs 7 K/microL) and bone marrow blasts (26% vs 50%) at presentation were lower than PPM1D-wt AML (P<0.05). PPM1D-mt patients had non-significantly higher response odds (OR = 1.68; 95% CI: 0.33–9.35) vs. wt. Compared to PPM1D-wt, PPM1D-mt had worse OS, with a median OS of 7.2 vs. 11 months and a 12-month OS 20% (95% CI 5.8- 69) vs. 47% (95% CI 43- 53) (log-rank P=0.041). PPM1D-mt were linked to a non-significant increase in mortality (HR = 1.87; 95% CI: 0.90–3.88) and shorter EFS (HR = 1.72; 95% CI: 0.83–3.53) on multivariable analysis. Conclusion TP53-mt remains a well-established predictor of poor prognosis in AML. Although PPM1D-mt is less common, it appears to be associated with a trend toward adverse outcomes, warranting further investigation. Notably, PPM1D-mt frequently co-occurs with TP53-mt and high-risk cytogenetic abnormalities, suggesting a potential synergistic effect. This co-occurrence may reflect a functionally compound heterozygous disruption of the p53 pathway.