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 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 and Lina Benajiba ()
Additional contact information
Nabih Maslah: Laboratoire de Biologie Cellulaire
Nina Kaci: Institut de Recherche Saint-Louis
Blandine Roux: Institut de Recherche Saint-Louis
Gabriela Alexe: Dana-Farber Cancer Institute and Boston Children’s Hospital
Raphael Marie: Institut de Recherche Saint-Louis
Hélène Pasquer: Institut de Recherche Saint-Louis
Emmanuelle Verger: Laboratoire de Biologie Cellulaire
Rafael Daltro Oliveira: INSERM
Cécile Culeux: Institut de Recherche Saint-Louis
Bochra Mlayah: Institut de Recherche Saint-Louis
Nicolas Gauthier: INSERM
Fanny Gonzales: Dana-Farber Cancer Institute and Boston Children’s Hospital
Lin-Pierre Zhao: Département d’hématologie et d’Immunologie
Saravanan Ganesan: Institut de Recherche Saint-Louis
Panhong Gou: Institut de Recherche Saint-Louis
Frank Ling: Institut de Recherche Saint-Louis
Juliette Soret-Dulphy: INSERM
Nathalie Parquet: Département d’hématologie et d’Immunologie
William Vainchenker: Département d’hématologie et d’Immunologie
Emmanuel Raffoux: Département d’hématologie et d’Immunologie
Rose Ann Padua: Institut de Recherche Saint-Louis
Stéphane Giraudier: Laboratoire de Biologie Cellulaire
Caroline Marty: Université Paris-Saclay
Isabelle Plo: Université Paris-Saclay
Camille Lobry: Institut de Recherche Saint-Louis
Kimberly Stegmaier: Dana-Farber Cancer Institute and Boston Children’s Hospital
Alexandre Puissant: Institut de Recherche Saint-Louis
Jean-Jacques Kiladjian: Institut de Recherche Saint-Louis
Bruno Cassinat: Laboratoire de Biologie Cellulaire
Lina Benajiba: Institut de Recherche Saint-Louis

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60884-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60884-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60884-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().