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

Abstract

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