Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome
Open accessAbstract
Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
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In mTP53 patients with >5% blasts, outcomes are poor independent of allelic state.
“Notably, in mTP53 patients with >5% blasts, outcomes have been shown to be poor, independent of allelic state, which has been validated by others.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [9]
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- Authors
- Grob, T., Al Hinai, A. S. A., Sanders, M. A., Kavelaars, F. G., Rijken, M., Gradowska, P. L., Biemond, B. J., Breems, D. A., Maertens, J., van Marwijk Kooy, M., Pabst, T., de Weerdt, O., Ossenkoppele, G. J., van de Loosdrecht, A. A., Huls, G. A., Cornelissen, J. J., Beverloo, H. B., Löwenberg, B., Jongen-Lavrencic, M., & Valk, P. J. M.
- Affiliations
- Erasmus MC (NL)
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands;
- Amsterdam University Medical Centers (NL)
- Department of Hematology, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium;
- Universitair Ziekenhuis Leuven (BE)
- Department of Hematology, Isala Hospital, Zwolle, The Netherlands;
- University Hospital of Bern (CH)
- Department of Hematology, Saint Antonius Hospital, Nieuwegein, The Netherlands;
- Department of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;
- University Medical Center Groningen (NL)
- Corresponding author
- Valk, Peter J. M.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2022-04-14
- Volume
- 139
- Issue
- 15
- Pages
- 2347-2354
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC11022827
- OpenAlex
- W4210694051
- Cited by
- 305
- References
- 25
- Citations by year
- 2026: 51 · 2025: 72 · 2024: 61 · 2023: 74 · 2022: 47
- FWCI
- 46.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Blood (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- European Hematology Association (TRTH182)
- KWF Kankerbestrijding (12507)
- Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung
- Erasmus Universitair Medisch Centrum Rotterdam
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- TP53 mutation, acute myeloid leukemia, high-risk myelodysplastic syndrome, variant allele frequency, co-occurring mutations, minimal residual disease, overall survival, prognostic factors, cytogenetics
- MeSH terms
- Cytogenetics, Humans, Mutation, Myelodysplastic Syndromes, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53
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