SF3B1is the most recurrently mutated RNA splicing factor in cancer; However, its study has been hindered by a lack of disease-relevant cell line models. Here, we compared four genome engineering platforms to establishSF3B1mutant cell lines: CRISPR-Cas9 editing, AAV HDR editing, base editing (ABEmax, ABE8e), and prime editing (PE2, PE3, PE5Max). We showed that prime editing via PE5max achieved the most efficientSF3B1K700E editing across a wide range of cell lines. We further refined our approach by coupling prime editing with a with a fluorescent reporter that leverages aSF3B1mutation-responsive synthetic intron to mark prime edited cells. Calling this approach prime editing coupled intron-assisted selection (PRECIS), we then introduced the K700E hotspot mutation into two chronic lymphocytic leukemia (CLL) cell lines, HG-3 and MEC-1, and demonstrated that our PRECIS-engineered cells faithfully recapitulate the altered splicing and copy number variation (CNV) events frequently found in CLL patients withSF3B1mutation. Our results showcase PRECIS as an efficient and generalizable method for engineering genetically faithfulSF3B1mutant models, shed new light on the role ofSF3B1mutation in cancer biology, and enables generation of novelSF3B1mutant cell lines in any cellular context.