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

作者：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 · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60884-1 · 被引用次数：9 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Acute Myeloid Leukemia Research、Eosinophilic Disorders and Syndromes

Abstract 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.