82: JAK2 inhibition drives RAS clonal selection in myelofibrosis

Maslah N et al., Nature Communications - Translational study showing ruxolitinib and JAK2 suppression select for RAS pathway–mutant clones in myelofibrosis, enhancing their fitness via MAPK activation and linking this selection to worse clinical outcomes in treated patients. Key terms: ruxolitinib, JAK2, RAS mutations, myelofibrosis, clonal evolution. Study Highlights:Longitudinal NGS of 143 myelofibrosis patients and targeted analyses show ruxolitinib exposure is associated with accumulation and increased VAF of NRAS/KRAS/CBL mutations compared with non-exposed patients. Single-cell DNA sequencing and ex vivo CD34+ assays demonstrate ruxolitinib selects RAS-mutant clones both inside and outside JAK/STAT-activated driver clones. In vitro and in vivo competition models and Jak2 knockdown reveal JAK2 inhibition increases RAS-mutant cellular fitness via MAPK pathway activation and release from oncogene-induced senescence. Clinically, RAS pathway mutations predict worse transformation-free and overall survival only in ruxolitinib-treated patients. Conclusion:JAK2 inhibition can promote selection and expansion of RAS-mutant clones in MPNs through MAPK-driven fitness advantages, supporting RAS screening and consideration of combinatorial strategies when using JAK inhibitors. Music:Enjoy the music based on this article at the end of the episode. Article title:JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms First author:Maslah N Journal:Nature Communications DOI:10.1038/s41467-025-60884-1 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ep82-jak2-inhibition-ras-selection-mpn QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-21. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering JAK2 inhibition, Ras/MAPK clonal selection, single-cell sequencing and ex vivo CD34+ cell data, in vivo murine competition models, clinical outcome associations, and therapeutic implications.- transcript topics: JAK-STAT signaling and JAK inhibitors; RAS pathway mutations and clonal selection (NRAS/KRAS/CBL); Single-cell sequencing and ex vivo CD34+ cell experiments; In vivo murine bone marrow competition and transplantation models; MAPK activation and rescue from oncogene-induced senescence; Clinical outcomes: transformation-free survival and overall survival QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Ruxolitinib exposure is associated with accumulation/selection of RAS pathway mutations (NRAS, KRAS, CBL) in myelofibrosis patients.- RAS mutations predict worse transformation-free survival and overall survival primarily in the context of ruxolitinib treatment.