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JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

ABSTRACT: Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication as it dramatically worsens disease prognosis. While sAML transformation is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F in sAML cases originating from JAK2-mutant MPNs suggests alternative mechanisms. Utilizing patient samples and in vivo modeling, we establish that sAML clones can emerge independently of JAK2-mutant cells. These leukemic clones undergo positive selection in the pro-inflammatory MPN environment leading to their predominance in the hematopoietic system. Genetic and pharmacological inhibition of IL-12 and TNFa 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE308233 | GEO | 2026/02/24

REPOSITORIES: GEO

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JAK2V617F Impairs Lymphoid Differentiation in Myeloproliferative Neoplasms

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