Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders

Purpose: PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under the selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear. Experimental Design: We characterized the clinical and genomic profiles of 112 PPM1D-mutated patients across the spectrum of myeloid disorders using a combination of bulk and single-cell analyses on diagnostic and longitudinal samples. Results: Among all patients, 78% had a history of primary cancer, with DNMT3A and TP53 being the most frequently comutated genes. In 10 patients with high-grade serous ovarian cancer, longitudinal analysis showed variable dynamics of PPM1D-mutant clones, with 81% of clones expanding during exposure to alkylating agents. Clonal hierarchy estimation revealed that 44% of patients with PPM1D-mutated AML had a PPM1D mutation in the founder clone, with rare TP53 comutations. Both patients with TP53 wild-type and TP53mutated AML had poor overall survival. Single-cell DNA and surface protein analysis in seven patients confirmed that PPM1D mutations can arise in the founding clone and are associated with the expression of leukemic markers. Conclusions: PPM1D mutations found in clonal hematopoiesis can spontaneously regress after treatment discontinuation; however, they can also be found in the dominant clone in AML/MDS.