Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms

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 that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional cooperating mutations, the absence of the JAK2V617F variant in some cases of sAML derived from JAK2V617F-mutant MPN suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemia-initiating clones driven by TET2 mutations can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Convergent profiling of mouse and human models identified IL-12 and TNFα as candidates providing extrinsic selective pressures and genetic and pharmacological inhibition of these cytokines mitigated the competitive advantage of TET2-mutant cells in an MPN background. These findings unveil therapeutic strategies to potentially prevent leukemic evolution in MPN patients by inhibiting specific cytokine signaling. Our data establish a new paradigm for clonal evolution of blood neoplasms by showing that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones independent of the primary disease.