JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms
- Nabih Maslah
- Nina Kaci
- Blandine Roux
- Gabriela Alexe
- Raphael Marie
- Hélène Pasquer
- Emmanuelle Verger
- Rafael Daltro De Oliveira
- Cécile Culeux
- Bochra Mlayah
- Nicolas Gauthier
- Fanny Gonzales
- Lin-Pierre Zhao
- Saravanan Ganesan
- Panhong Gou
- Frank Ling
- Juliette Soret-Dulphy
- Nathalie Parquet
- William Vainchenker
- Emmanuel Raffoux
- Rose Ann Padua
- Stéphane Giraudier
- Caroline Marty
- Isabelle Plo
- Camille Lobry
- Kimberly Stegmaier
- Alexandre Puissant
- Jean-Jacques Kiladjian
- Bruno Cassinat
- Lina Benajiba
2025-07-07
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.