Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis
Menée à partir de l'analyse du génome entier ou ciblé de 30 patients atteints d'une néoplasie myéloproliférative sans anomalie chromosomique de Philadelphie et à partir d'une analyse phylogénétique de 203 génomes entiers de colonies hématopoïétiques, cette étude examine l'évolution génétique de ce type de néoplasie ainsi que la mutagenèse liée aux traitements
Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.
Cancer Discovery , résumé, 2026