TP53-Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm - Distinct Mutation Leads to Poorer Prognosis

Q: How were TP53 mutations analyzed and compared across AML and blast phase MPN-BP?

A retrospective cohort of 39 TP53-mutated patients (23 AML and 16 MPN-BP) was analyzed to characterize mutation patterns and relate them to clinical outcomes.

Q: What mutation features were linked to worse overall survival?

High-risk TP53 mutations included splice-site variants (notably c.376), missense mutations such as p.R175H, and mutations in the oligomerization domain, which were associated with particularly poor OS (under 3 months).

Q: How do the proposed risk groups differ in prognosis?

A two-tiered risk stratification was proposed: the high-risk group showed substantially worse survival (median OS about 1.3 months), while the low-risk group with selected missense variants (notably in exons 6–7 and some transactivation domain mutations) had relatively better outcomes (median OS about 10.15 months).

Sep 23, 2026

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Patients carrying TP53 mutations in acute myeloid leukemia (AML) and blast phase myeloproliferative neoplasms (MPN-BP) show similarly adverse clinical outcomes. Retrospective evaluation of 39 TP53-mutated patients (23 AML; 16 MPN-BP) identified 47 distinct TP53 mutations with prognostic relevance. High-risk mutations, including splice-site variants and specific missense changes, correlated with markedly worse overall survival (OS < 3 months), whereas selected single missense variants in exons 6–7 and transactivation domain changes associated with better prognosis. These results support mutation-specific cellular effects and therapeutic response differences, motivating prioritized research and targeted treatment strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages7

Reading Time18 min

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Introduction

TP53 mutations as independent risk factors

Mutation patterns and hotspot prevalence

Mechanisms of TP53 dysfunction

Clinical context in myeloid neoplasms

Definitions and disease classification (ICC 2022 and WHO HAEM5)

European Journal of Haematology ORIGINAL ARTICLE OPEN ACCESS TP53-Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm: Distinct Mutation Leads to Poorer Prognosis Dong Chen1 | Miguel Cantu2 | Alexa Siddon3,4 | Olga K. Weinberg2 1Department of Pathology and Laboratory Medicine, University of Connecticut, Farmington, Connecticut, USA | 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA | 3Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, USA | 4Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA Correspondence: Olga K. Weinberg ([olga.weinberg@utsouthwestern.edu](olga.weinberg@utsouthwestern.edu)) Received: 20 January 2025 | Revised: 19 March 2025 | Accepted: 20 March 2025 Keywords: acute myeloid leukemia with mutated TP53 | AML-TP53 | blast phase myeloproliferative neoplasm with mutated TP53 | MPN-BP-TP53 | TP53 mutation ABSTRACT Patients with TP53 mutations in acute myeloid leukemia (AML) and blast phase myeloproliferative neoplasms (MPN-BP) experience similar poor clinical outcomes. A retrospective analysis of 39 patients with TP53 mutations (23 with AML and 16 with MPN-BP) revealed comparable mutation patterns associated with prognostic significance. A total of 47 distinct TP53 mutations were identified, including seven patients with multiple mutations. Based on clinical outcomes, we propose a two-tiered risk stratification for TP53-mutated AML and MPN-BP. The high-risk group mutations, such as splice site variants in Intron 4 (especially c.376), missense mutations in Exon 5 (notably p.R175H), and mutations in the oligomerization domain (OD), were associated with, particularly, worse overall survival (OS < 3months). Conversely, single missense mutations in Exons 6 and 7 (notably p.Y220C, p.R248N, p.R248Q, and p.R248W), and mutations in the transactivation domain (TAD), constituted a low-risk group and were associated with relatively better prognosis (median OS: 10.15 months for the low-risk group vs. 1.3 months for the highrisk group, p < 0.0001) . These findings support the hypothesis that distinct TP53 mutations can lead to varying cellular effects, therapeutic responses, and clinical outcomes. Consequently, acute myeloid neoplasms (AML and MPN-BP) harboring certain TP53 mutations may exhibit increased aggressiveness compared to other TP53 mutants, underscoring the need for prioritized clinical research and therapeutic targeting. 1 | Introduction Regardless of coexisting genetic alterations, TP53 mutations serve as an independent risk factor associated with poor clinical outcomes. As the most frequently mutated gene in human cancers (detected in 50%–60%), TP53 mutations are dominated by missense mutations (90%), involving up to 190 different codons primarily localized in the DNA binding domain (DBD, aminoacid residues 102–292) [1] . Among these, the Top 10 hotspot mutations (p.V157F, p.R175H, p.Y220C, p.G245S, p.R248W, p.R248Q, p.R249S, p.R273C, p.R273H, p.R282W) account for up to 30% of all TP53 mutations [1]. The frequency of these hotspot mutations varies across different cancer types [2] . TP53 mutations have been detected in 10.5% of acute myeloid leukemia (AML)/myelodysplastic syndrome with excess blasts (MDS-EB) patients, with a median variant allele frequency (VAF) of 47% and a 2-year overall survival (OS) rate of 12.8%[3] . The pathogenesis associated with TP53 mutation involves complex mechanisms that lead to manipulation ofTP53 protein function in various ways. These include distinct forms of mutated TP53 protein that can exhibit loss-of-function (LOF) and/or dominant-negative This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

FAQs

How were TP53 mutations analyzed and compared across AML and blast phase MPN-BP?

A retrospective cohort of 39 TP53-mutated patients (23 AML and 16 MPN-BP) was analyzed to characterize mutation patterns and relate them to clinical outcomes.

What mutation features were linked to worse overall survival?

High-risk TP53 mutations included splice-site variants (notably c.376), missense mutations such as p.R175H, and mutations in the oligomerization domain, which were associated with particularly poor OS (under 3 months).

How do the proposed risk groups differ in prognosis?

A two-tiered risk stratification was proposed: the high-risk group showed substantially worse survival (median OS about 1.3 months), while the low-risk group with selected missense variants (notably in exons 6–7 and some transactivation domain mutations) had relatively better outcomes (median OS about 10.15 months).

Sep 23, 2026

Uploaded by Angel