️ Episode 82: JAK2 Inhibition Drives RAS Pathway Mutant Clonal Selection in Myeloproliferative Neoplasms

In this episode of PaperCast Base by Base, we explore how JAK2 inhibition by ruxolitinib reshapes clonal dynamics in myelofibrosis by mediating the expansion of RAS pathway-mutated clones in myeloproliferative neoplasms.

Study Highlights:

We conducted a longitudinal molecular analysis of myelofibrosis patients treated with ruxolitinib and observed a marked accumulation of RAS pathway mutations following JAK2 inhibitor exposure. Single-cell DNA sequencing and ex vivo treatment of patient-derived CD34+ cells demonstrated that ruxolitinib selectively enriches RAS-mutant clones even in the absence of JAK/STAT hyperactivation. Competitive co-culture and in vivo models revealed that RAS-mutated cells exhibit increased fitness and clonogenic potential under JAK2 inhibition. Mechanistic studies showed that JAK2 downregulation leads to MAPK pathway activation, which underlies the enhanced oncogenic potential of RAS-mutant clones.

Conclusion:

These insights highlight the need for pre-treatment screening of RAS mutations and support the development of combination strategies targeting both JAK/STAT and MAPK pathways to prevent clonal resistance.

SEO Keywords: genomics, what is genomics, graduate studies in genomics, functional genomics, structural genomics, genomics and proteomics

Episode Slug: jak2-inhibition-drives-ras-pathway-mutant-clonal-selection

Reference:

Maslah N, Kaci N, Roux B, et al. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms. Nat Commun. 2025;16:6270. doi:10.1038/s41467-025-60884-1

License:

This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.