The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis

Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) - a condition termed clonal hematopoiesis (CH) - are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.

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Publication Details

Journal
Leukemia
Published
2025-12-17
DOI
https://doi.org/10.1038/s41375-025-02839-5
Citations
2
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
3.54

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article

The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis

Nancy Klemm, Markus Gabriel Manz, Christian Koch, Jonas Fullin et al.
2 citations
Leukemia
Acute Myeloid Leukemia Research
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article

The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis

Nancy Klemm, Markus Gabriel Manz, Christian Koch, Jonas Fullin, Massimo Lopes, Karolina Zielińska, Philip H. Jones, Marco M. Bühler, Francisco Caiado, Lubor Borsig, Kari J. Kurppa, Joëlle Tchinda, Melissa Lock, Steffen Boettcher, Roman R. Schimmer, Cyril Doerdelmann, Ebru Topçu
article en
2 citations

Abstract

Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) - a condition termed clonal hematopoiesis (CH) - are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.

LeukemiaVol. 40(2)
University of Turku (FI), University of Zurich (CH), University of Cambridge (GB), Wellcome Sanger Institute (GB), University Hospital of Zurich (CH), University Children's Hospital Zurich (CH), Hutchinson (United Kingdom) (GB), Immunologie-Zentrum Zürich (CH)
National Science Foundation, Cancer Research UK, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universität Zürich, Helmut Horten Stiftung, Functional Genomics Center Zurich
Openalex Percentile: Top 6%
Acute Myeloid Leukemia Research
3.54
DOIOpen Access PDFOpenAlex
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