101: JAK2 Inhibition Selects RAS-Mutant Clones in Myelofibrosis

️Episode 101: JAK2 Inhibition Selects RAS-Mutant Clones in Myelofibrosis In this episode of PaperCast Base by Base, we explore how JAK2 inhibition with ruxolitinib can reshape clonal architecture in myeloproliferative neoplasms (MPN), favoring outgrowth of RAS‑pathway mutant subclones and altering patient outcomes. We situate these findings within the broader landscape of genomics, functional and structural genomics, and proteomics—touching on themes like gene–disease association, variant interpretation, and resistance mechanisms in targeted therapies. Study Highlights:Using a longitudinal myelofibrosis cohort with paired molecular evaluations, the authors show that patients exposed to ruxolitinib preferentially acquire or expand RAS pathway mutations, with variant allele frequencies increasing over time and a higher prevalence of multiple RAS‑mutant clones; in contrast, such enrichment is uncommon in untreated patients and RAS status predicts poorer overall and transformation‑free survival only under ruxolitinib exposure. Single‑cell DNA sequencing and ex vivo treatment of primary CD34+ cells demonstrate that RAS‑mutant clones gain a fitness advantage under JAK/STAT inhibition in both wild‑type and hyper‑activated JAK/STAT contexts, while canonical MPN driver allele burdens often decline. In vitro and in vivo competition assays, alongside shRNA‑mediated JAK2 knockdown, show increased proliferation and clonogenicity of RAS‑mutant cells during JAK2 inhibition, and co‑treatment with a MEK inhibitor partially reverses this advantage. Mechanistically, MAPK pathway activation and JAK2 downregulation correlate with release from oncogene‑induced senescence and increased cell‑cycle progression in RAS‑mutant cells, and external datasets further associate RAS alterations with resistance to multiple JAK2 inhibitors. Conclusion:Screening for pre‑existing RAS pathway mutations and monitoring clonal evolution during JAK2‑inhibitor therapy may inform risk, guide combination strategies, and ultimately improve MPN patient management. Reference:Maslah N, Kaci N, Roux B, Alexe G, Marie R, Pasquer H, Verger E, Daltro De Oliveira R, Culeux C, Mlayah B, Gauthier N, Gonzales F, Zhao L‑P, Ganesan S, Gou P, Ling F, Soret‑Dulphy J, Parquet N, Vainchenker W, Raffoux E, Padua RA, Giraudier S, Marty C, Plo I, Lobry C, Stegmaier K, Puissant A, Kiladjian J‑J, Cassinat B, Benajiba L. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms. Nature Communications. 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.   Chapters (00:00:14) - Papercast: The dynamic dance of cancer biology(00:01:56) - JEK-inhibitors: The precision of their targeting(00:07:19) - Ruxolitinib and the Ras mutation(00:12:52) - JAK2 inhibition in metastatic pancreatic cancer(00:17:00) - The oncogene overdose or paradoxical selection