Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.
Key claim: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation via distinct evolutionary routes (TP53 loss, stepwise drivers, or independent leukemic clones), while hydroxycarbamide and azacitidine leave characteristic mutational signatures and some triple-negative ET cases appear non-neoplastic.
Abstract
UNLABELLED: 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. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.
Why this matters
This is the first large longitudinal whole-genome sequencing integration of clonal phylogenies with serial blood counts in MPN, showing that the trajectory toward myelofibrotic and leukemic transformation is genomically encoded years before it becomes clinically visible — and that it takes at least three distinguishable evolutionary routes. It also provides direct in-human evidence that hydroxycarbamide and azacitidine imprint characteristic mutational signatures on MPN hematopoiesis, and that some triple-negative ET may not be neoplastic at all, each of which reshapes how specific subtypes should be tracked and treated over decades.