Novel scheme for defining the clinical implications of TP53 mutations in myeloid neoplasia
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Abstract
Background: TP53 mutations ( TP53 MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely. Results: Overall, TP53 MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53 MT . Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases. Conclusion: Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.
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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 [7]
The Results (Clinical characteristics of patients’ cohort; page unavailable) define high-risk MDS by a blast count of ≥5%, but do not report that outcomes above this threshold are poor regardless of allelic state. Instead, the Results (Different TP53 configurations and disease subtypes impact prognosis; page unavailable) report worse survival for double-hit than single-hit TP53 mutations, including in the MDS analysis. The claimed independence from allelic state is therefore not supported. (LLM, conf=0.83)
Experimental — accuracy not yet measuredmTP53 patients with high VAF (>20-23%), biallelic state, and/or complex karyotype have particularly poor risk.
“Specifically, mTP53 patients with a high variant allele frequency (VAF; i.e., >20%–23%), biallelic state, and/or complex karyotype (CK) have particularly poor risk.”
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 [7]
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Evidence-based risk stratification of myeloid neoplasms harboring <i>TP53</i> mutations
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- Authors
- Bahaj, W., Kewan, T., Gurnari, C., Durmaz, A., Ponvilawan, B., Pandit, I., Kubota, Y., Ogbue, O. D., Zawit, M., Madanat, Y., Bat, T., Balasubramanian, S. K., Awada, H., Ahmed, R., Mori, M., Meggendorfer, M., Haferlach, T., Visconte, V., & Maciejewski, J. P.
- Affiliations
- Cleveland Clinic (US)
- University of Rome Tor Vergata (IT)
- The University of Texas Southwestern Medical Center (US)
- Wayne State University (US)
- Munich Leukemia Laboratory (Germany) (DE)
- Corresponding author
- Visconte, Valeria
- Maciejewski, Jaroslaw P.
- ORCID
- Venue
- Journal of Hematology & Oncology
- Published
- 2023-08-03
- Volume
- 16
- Issue
- 1
- Pages
- 91-91
- ISSN
- 1756-8722 (ISSN-L)
- PMC
- PMC10401750
- OpenAlex
- W4385554312
- Cited by
- 45
- References
- 31
- Citations by year
- 2026: 17 · 2025: 13 · 2024: 13 · 2023: 2
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Hematology & Oncology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Case Western Reserve University
- Edward P. Evans Foundation
- Vera and Joseph Dresner Foundation (R35HL135795)
- National Heart, Lung, and Blood Institute (R01HL118281, R35HL135795, R01HL132071, R01HL123904)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- TP53 mutation, myeloid neoplasms, biallelic inactivation, monoallelic variants, prognostic model, overall survival, acute myeloid leukemia, myelodysplastic syndrome, genetic mosaicism, single-cell DNA sequencing
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