What Is the Prognostic Impact of JAK2V617F VAF and High Molecular Risk Mutations in Myelofibrosis?

Lower JAK2V617F variant allele frequency (VAF) and high molecular risk (HMR) mutations such as ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157 are known to be associated with poor prognosis for patients with myelofibrosis (MF), but what is the relationship between JAK2V617F VAF and HMR mutations?

A study published in Leukemia evaluated the prognostic impact of concurrent JAK2V617F VAF and HMR mutations in MF.

Using targeted next-generation sequencing, the researchers analyzed the mutation status of 54 myeloid neoplasm–relevant genes in 124 patients. Among patients with JAK2 mutations, concurrent HMR mutations were associated with poor prognosis in those with lower JAK2V617F VAF, but not in those with higher JAK2V617F VAF.

A multivariable analysis revealed that harboring both HMR mutations and a lower JAK2V617F VAF were independent adverse prognostic factors for survival regardless of age, Myeloproliferative Neoplasm International Prognostic Score system (MIPSS) 70, MIPSS70 + v2, and Genetically Inspired Prognostic Scoring System (GIPSS) risk groups.

Prognostic models were also improved with the incorporation of HMR mutations and JAK2V617F VAF status of 50% or less, as shown by higher C-indexes and time-dependent receiver operating characteristic (ROC) analyses.

“Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics,” the researchers concluded.

Reference

Wang YH, Wei CH, Lin CC, et al. Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis—insights from a multicenter study. Leukemia. 2025;39:144-154. doi:10.1038/s41375-024-02422-4