Clonal Evolution of <i>PPM1D</i> Mutations in the Spectrum of Myeloid Disorders
David Fandrei, Jean Pegliasco, Florence Pasquier, Nathalie Ibrahim, Maria Kfoury, Céline Berthon, Maël Heiblig, Delphine Lebon, Ambroise Marçais, Mathieu Meunier, Ahmad Al Jijakli, Émilie Lemasle, Sylvain Chantepie, Cécile Pautas, Pierre‐Yves Dumas, Célia Salanoubat, Diana Carp, Romain Loyaux, Cyril Quivoron, Arnaud Pagès, Bastien Job, Remy Jelin, Gérôme Jules-Clément, Iléana Antony‐Debré, Aline Renneville, Sophie Cotteret, Raphaël Itzykson, Hervé Dombret, Nicolas Duployez, Nathalie Droin, Alexandra Léary, Christophe Marzac, Elsa Bernard, Jean‐Baptiste Micol
Abstract
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 TP53-mutated 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.