2. Academic Validation
  3. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms

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

  • Nat Commun. 2025 Jul 8;16(1):6270. doi: 10.1038/s41467-025-60884-1.
Nabih Maslah # 1 2,  Nina Kaci # 3,  Blandine Roux # 3,  Gabriela Alexe 4,  Raphael Marie 3,  Hélène Pasquer 3 5,  Emmanuelle Verger 1 2,  Rafael Daltro De Oliveira 5,  Cécile Culeux 3,  Bochra Mlayah 2,  Nicolas Gauthier 5,  Fanny Gonzales 4,  Lin-Pierre Zhao 6,  Saravanan Ganesan 2,  Panhong Gou 2,  Frank Ling 3,  Juliette Soret-Dulphy 5,  Nathalie Parquet 6,  William Vainchenker 6,  Emmanuel Raffoux 6,  Rose Ann Padua 2,  Stéphane Giraudier 1 2,  Caroline Marty 7,  Isabelle Plo 7,  Camille Lobry 3,  Kimberly Stegmaier 4,  Alexandre Puissant 3,  Jean-Jacques Kiladjian 2 5,  Bruno Cassinat 1 2,  Lina Benajiba 8 9
Affiliations

Affiliations

  • 1 Université Paris Cité, APHP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris, France.
  • 2 INSERM UMR 1131, Institut de Recherche Saint-Louis, Paris, France.
  • 3 INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
  • 5 Université Paris Cité, APHP, Hôpital Saint-Louis, Centre d'Investigations Cliniques, INSERM, CIC 1427, Paris, France.
  • 6 Université Paris Cité, APHP, Hôpital Saint-Louis, Département d'hématologie et d'Immunologie, Paris, France.
  • 7 INSERM UMR 1287, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 8 INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France. lina.benajiba@inserm.fr.
  • 9 Université Paris Cité, APHP, Hôpital Saint-Louis, Centre d'Investigations Cliniques, INSERM, CIC 1427, Paris, France. lina.benajiba@inserm.fr.
  • # Contributed equally.
PMID: 40623967 DOI: 10.1038/s41467-025-60884-1
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.

Figures
Products