MPN clonal evolution trajectories to transformation

Current understanding

Longitudinal whole-genome sequencing of MPN patients reveals that progression to myelofibrosis or acute leukemia follows distinct, genomically encoded evolutionary routes — TP53 biallelic loss, stepwise accumulation of high-risk co-mutations on the driver clone, or emergence of a phylogenetically independent leukemic clone — with clonal phylogenies detectable years before clinical transformation. This reframes MPN progression as a trajectory whose fate is largely written in the marrow clonal architecture well ahead of overt phenotypic change, motivating serial molecular surveillance as a lead indicator of disease direction.

Evidence log

• 2026-10-07 — Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms.: CALR-mutated MPN outcome study supports the stepwise high-risk co-mutation accrual trajectory (TP53/KRAS/RUNX1 on the CALR driver clone) as the dominant prognostic axis, motivating serial molecular profiling to detect trajectory shifts in real time. (novelty: 3)
• 2026-09-19 — Clinicopathologic Characteristics of SomaticMutations in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Systematic Review.: Pooled synthesis finds a near 50/50 split between single-hit and multi-hit TP53 configurations in MPN with multi-hit status worsening OS only in chronic-phase disease, suggesting the biallelic TP53 trajectory exerts its prognostic weight before overt transformation rather than after. (novelty: 3)
• 2026-07-01 — Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis.: Cross-sectional NGS of post-PV/post-ET MF shows that ASXL1 and UTS (U2AF1/TP53/SRSF2) co-mutations layered on the driver clone stratify overall survival, consistent with stepwise high-risk co-mutation accrual as a genomically encoded route toward adverse outcomes in secondary MF. (novelty: 3)
• 2026-09-01 — Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.: cross-connection with blast-phase-mpn-leukemic-transformation: Blast-phase MPN can arise from a phylogenetically independent leukemic clone rather than direct evolution of the chronic-phase MPN driver clone, one of three distinct evolutionary routes to transformation. (novelty: 4)

Open questions

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