Genetic evolution of myeloproliferative neoplasms from chronic phase to blastic phase: An analysis of 46 paired...

Clonal evolution drives progression of myeloproliferative neoplasms (MPN) from chronic phase (CP) to blastic phase (BP).

Targeted next-generation sequencing of 46 paired MPN-CP/BP samples was performed to assess clonal evolution through variant allele frequency changes.

The median time from MPN-CP to BP was 6.9 (range 0.3-27.8) years. In MPN-CP, driver mutation frequency was 98% (JAK2-V617F 67%, CALR 28%, MPL 2%), decreased to 78% in BP due to JAK2-V617F loss, with all CALR mutations preserved. Total mutation numbers increased during BP progression (median 2 in CP vs. 3 in BP, p < .001). Epigenetic mutations (TET2 24%, DNMT3A 17%, ASXL1 15%, EZH2 11%) were common in CP and persisted or expanded in BP, with occasional acquisition of ASXL1 (p = .074), EZH2, and IDH1/2 mutations. Spliceosome mutations rose from 26% to 39% and transcription-related mutations from 13% to 33%. RUNX1, TP53, and most signaling gene mutations emerged predominantly in BP. JAK2-V617F, often preceded by TET2, ASXL1, DNMT3A, or EZH2 mutations, persisted or was replaced by other subclones in BP. Female and JAK2-V617F loss were linked to shorter time to BP and poorer survival from CP. Survival after BP was lower in patients acquiring signaling mutations but improved with hematopoietic stem cell transplantation.

MPN transformation involves complex clonal evolution, with frequent clonal hematopoiesis-related mutations preceding driver mutations, preserved CALR, acquisition of TP53, RUNX1 and signaling mutations, and JAK2-V617F loss linked to poorer survival during BP transformation, which may influence therapeutic decisions.