JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms
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.
Article Details
Authors (30)
Nabih Maslah
Nina Kaci
Blandine Roux
Gabriela Alexe
Department of Pediatric Oncology, Dana-Farber Cancer Institute
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
INSERM Unité Mixte de Recherche 1287, Villejuif, France
Camille Lobry
Kimberly Stegmaier
Department of Pediatric Oncology, Dana-Farber Cancer Institute
Alexandre Puissant
Jean-Jacques Kiladjian
Bruno Cassinat
Lina Benajiba