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
  • 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. [email protected].
  • 9. Université Paris Cité, APHP, Hôpital Saint-Louis, Centre d'Investigations Cliniques, INSERM, CIC 1427, Paris, France. [email protected].
  • # 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.

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