Functional consequences of SF3B1 co-mutation in AML with inv(3) or t(3;3). In a cohort of 109 patients with inv(3)/t(3;3) AML, mutations in the core RNA splicing factor, SF3B1, were identified in >30% of patients (bottom left). Coexpression of humanized inv(3) and mutant Sf3b1 causes increased death from leukemia compared with inv(3) alone in transgenic mice (bottom right). Aberrant mRNA splicing by mutant SF3B1 causes the insertion of 18 nucleotides between exons 12 and 13 of the transcription factor EVI1. This novel isoform, EVI1 + 18, binds to different regions of the genome, leading to the increased expression of genes associated with leukemogenesis (top). Figure created with BioRender.com.