Genomic evolution and natural history of myeloproliferative neoplasms on therapy
Menée à l'aide d'échantillons sanguins, d'échantillons de moelle osseuse et d'une analyse phylogénétique à partir de 203 génomes entiers de colonies hématopoïétiques, cette étude démontre que la progression d'une néoplasie myéloproliférative vers une leucémie est génétiquement prédéterminée des années à l'avance par des évolutions clonales spécifiques et identifie des mutations associées à l'azacitidine et à l'hydroxycarbamide
Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. 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 leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia 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 progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.
Cancer Discovery , article en libre accès, 2026