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 (CH), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under 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 frequent co-mutated genes. In ten 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 PPM1D-mutated acute myeloid leukemia (AML) patients had a PPM1D mutation in the founder clone, with rare TP53 co-mutations. Both TP53 wildtype and mutated AML patients 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 were associated with expression of leukemic markers.

Conclusions: PPM1D mutated CH clones can spontaneously regress after treatment discontinuation, however they can also be found in the dominant clone in AML/MDS.