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bioRxiv · 10.1101/2025.09.23.678057

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

Parsons, T. M.·Krishnan, A.·Xavier Raj, I.·Young, A. L.·O'Leary, D. R.·Arand, J.·Cox, M.·Oh, S. T.·Challen, G. A.
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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 that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F 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 TNF 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.

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Parsons, T. M., Krishnan, A., Xavier Raj, I., Young, A. L., O'Leary, D. R., Arand, J., Cox, M., Oh, S. T., Challen, G. A.. 2025-09-25. JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones. https://doi.org/10.1101/2025.09.23.678057

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