Targeting of the splicing factor YBX1 or MKNK1/ERK-signaling resolved the persistence of JAK2-V617F mutant cells under JAK-inhibitor therapy while leaving cellular fitness in the absence of the drug largely unaffected, demonstrating that JAK-dependent control of oncogenic mRNA splicing is a critical function specifically for the phenomenon of MPN persistence under kinase inhibitor exposure. Here, JAK2 is linked to myeloproliferative disorder.