Mutation patterns associated with leukemic transformation of MPN

Leukemic transformation (LT) is the main cause of death for patients with myeloproliferative neoplasms (MPNs). To study genetic changes associated with the LT, we performed targeted sequencing in 26 MPN patients including 21 with paired samples. We observed that, besides three driver genes (JAK2, MPL, and CALR), IDH2 (19%) and ASXL1 (14%) were also frequently mutated at MPN diagnosis. Although the allelic burden of mutations in DNA methylation and spliceosome did not expand during LT, they were enriched in patients with LT (LT group), suggesting these mutations may be potential predictive markers for LT. In follow-up samples, we also observed acquisition of mutations in genes such as ASXL1, TP53, IDH1, RUNX1, and SETBP1, mostly in the LT group. When considering the changes in allelic burden from diagnosis to follow-up samples, allelic burdens of mutated genes in the LT group expanded including mutations in the activated signaling pathway (median allelic burden, 36.7% to 43.7%, p=0.045). In contrast, the dynamics of mutation in patients with no clinical progression was subtle compared to the LT group (median allelic burden, 36.3% to 35.7%, p=0.739). Overall, the present study demonstrates genetic changes during LT and provides the potential for prognostic application.