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<p>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 <i>TP53</i>-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 <i>TP53</i>-mutant t-AML/MDS, especially the role of the <i>TP53</i> 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 <i>Trp53</i> mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic <i>Trp53</i> mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic <i>Trp53</i> mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as <i>MDM2</i> overexpression, can replicate the effects of biallelic <i>TP53</i> mutations, providing a possible explanation for cases of <i>TP53</i>-mutant AML/MDS that retain one wild-type <i>TP53</i> allele. Our findings elucidate the pathogenesis of <i>TP53</i>-mutant t-AML/MDS and support the classification of biallelic <i>TP53</i>-mutant AML/MDS as distinct clinical entities.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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

摘要

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.