biostudies-literatureUnknownParsons TMNIDDK NIH HHSNHLBI NIH HHSNCI NIH HHSMyeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2 V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2 V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNFα mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.bioRxiv : the preprint server for biology2025.09.23.678057https://www.ebi.ac.uk/biostudies/studies/S-EPMC12485877biostudies-literatureJAK2 V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.PMC12485877R01 HL147978R01 HL134952P30 CA091842R01 CA236819K99 CA296777R01 DK124883T32 HL007088Raj IXChallen GAOh STYoung ALParsons TMArand JKrishnan ACox MO'Leary DRfalseJAK2 V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2 V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2 V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNFα mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.2025-01-01T00:00:00Z2025 Sep2026-05-08T03:18:24.419Z2026-05-08T03:10:27.35ZS-EPMC124858774104040910.1101/2025.09.23.678057