Ppm1d Mutations Are Rare In De Novo And Therapy-Related Acute Myeloid Leukemia

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in peripheral blood mononuclear cells (PBMC) of otherwise healthy adults that has been associated with increased risk of developing hematological malignancies. Clonal hematopoiesis has been shown to be present in patients with therapy-related myeloid neoplasms (therapy-related acute myeloid leukemia, t-AML) / therapy-related myelodysplastic syndrome, t-MDS) at the time of their primary cancer diagnosis and before exposure to treatment. Such clones expand under selective pressure from cytotoxic treatment for the primary cancer and can subsequently give rise to overt myeloid neoplasms. Somatic mutations in the gene encoding the TP53-inducible protein phosphatase Mg2+/Mn2+ 1D (PPM1D) were initially reported in PBMC of patients with solid tumors (breast, ovary, lung) and lymphoma. They are associated with older age and seem to reflect prior exposure to cytotoxic treatment. Moreover, the mutations, all of which are nonsense or frameshift mutations in exon 6, have been described as one of the most recurrent mutations in CHIP and to be frequent in t-MDS.