Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms

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 cooperating mutations, the absence of the JAK2 ^V617F variant in some cases of sAML derived from JAK2 ^V617F-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.