JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms

JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib’s impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations.

Single-cell DNA sequencing combined with ex vivo treatment of RAS mutated CD34+ primary patient cells, demonstrates that ruxolitinib induces RAS clonal selection both in a JAK/STAT wild-type and hyper-activated context.

RAS mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of RAS-mutated cells under ruxolitinib or JAK2 knock-down, consistent with an on-target effect. MAPK pathway activation is associated with JAK2 downregulation resulting in enhanced oncogenic potential of RAS mutations.

Our results prompt screening for pre-existing RAS mutations in JAK inhibitor treated patients with MPN.

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Nature Communication 2025

Nabih Maslah, Nina Kaci, Blandine Roux, Gabriela Alexe,

JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib’s impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations.

Single-cell DNA sequencing combined with ex vivo treatment of <i>RAS</i> mutated CD34<sup>+</sup> primary patient cells, demonstrates that ruxolitinib induces <i>RAS</i> clonal selection both in a JAK/STAT wild-type and hyper-activated context.

<i>RAS</i> mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of <i>RAS-</i>mutated cells under ruxolitinib or <i>JAK2</i> knock-down, consistent with an on-target effect. MAPK pathway activation is associated with <i>JAK2</i> downregulation resulting in enhanced oncogenic potential of <i>RAS</i> mutations.

Our results prompt screening for pre-existing <i>RAS</i> mutations in JAK inhibitor treated patients with MPN.

<a href= »https://www.nature.com/articles/s41467-025-60884-1″>Voir la publication</a>