Therapy-Induced Clonal Selection as a Driver of Response to JAK Inhibitors in Myelofibrosis

Rontauroli, S.; Carretta, C.; Bertesi, M.; Parenti, S.; Benati, D.; Maccaferri, M.; Ferrari, T.; Malerba, M.; Neroni, A.; Papa, E.; Norfo, R.; Mirabile, M.; Tavernari, L.; Tombari, C.; Guglielmelli, P.; Recchia, A.; Potenza, L.; Maffei, R.; Tagliafico, E.; Luppi, M.; Vannucchi, A. M.; Manfredini, R.

doi:10.64898/2026.06.20.733514

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bioRxiv · 10.64898/2026.06.20.733514

Therapy-Induced Clonal Selection as a Driver of Response to JAK Inhibitors in Myelofibrosis

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Abstract

Myelofibrosis (MF) originates from the stepwise acquisition of somatic mutations in Hematopoietic Stem and Progenitor Cells (HSPCs). Alongside driver events triggering JAK-STAT pathway hyperactivation, several additional mutations, usually affecting the epigenetic machinery, contribute defining therapeutic response. Specifically, JAK-inhibition (JAKi) relieves MF symptoms but rarely eradicates the neoplastic clone. To elucidate clonal dynamics associated with JAKi, we conducted a longitudinal single-cell proteogenomic study on 6 responders and 6 non-responders MF patients. Mutational analysis revealed that the mutation acquisition order determines JAKi sensitivity. Indeed, driver-only clones are highly sensitive to JAKi, while co-mutated clones persist after treatment. JAKi response is mainly limited to the differentiated myeloid compartment, while mutant HSPCs are often maintained in JAKi-responders. Co-mutated clones may evade JAKi and outcompete other neoplastic cell populations, thus contributing to disease persistence.

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Rontauroli, S., Carretta, C., Bertesi, M., Parenti, S., Benati, D., Maccaferri, M., Ferrari, T., Malerba, M., Neroni, A., Papa, E., Norfo, R., Mirabile, M., Tavernari, L., Tombari, C., Guglielmelli, P., Recchia, A., Potenza, L., Maffei, R., Tagliafico, E., Luppi, M., Vannucchi, A. M., Manfredini, R.. 2026-06-23. Therapy-Induced Clonal Selection as a Driver of Response to JAK Inhibitors in Myelofibrosis. https://doi.org/10.64898/2026.06.20.733514

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