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

Fullin, Jonas; Topçu, Ebru; Zielińska, Karolina A.; Schimmer, Roman R.; Klemm, Nancy; Koch, Christian; Caiado, Francisco; Lock, Melissa; Doerdelmann, Cyril; Bühler, Marco M.; Tchinda, Joelle; Kurppa, Kari J.; Borsig, Lubor; Jones, Philip H.; Lopes, Massimo; Manz, Markus G.; Boettcher, Steffen
The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis

Fullin, Jonas
Topçu, Ebru
Zielińska, Karolina A.
Schimmer, Roman R.
Klemm, Nancy
Koch, Christian
Caiado, Francisco
Lock, Melissa
Doerdelmann, Cyril
Bühler, Marco M.
Tchinda, Joelle
Kurppa, Kari J.
Borsig, Lubor
Jones, Philip H.
Lopes, Massimo
Manz, Markus G.
Boettcher, Steffen
Katso/Avaa
Lataukset: 

Springer Nature
doi:10.1038/s41375-025-02839-5
URI
https://doi.org/10.1038/s41375-025-02839-5
Näytä kaikki kuvailutiedot
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe202601215541
Tiivistelmä

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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