ZRSR2 is a zinc finger RNA-binding protein essential for pre-mRNA splicing of both U2- and U12-type introns. It selectively binds the 3'-splice site of pre-mRNAs and is required for spliceosomal complex assembly and U2 intron splicing completion 1. ZRSR2 functions as a tumor suppressor; mutations occur frequently in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), affecting approximately 45-85% of myeloid neoplasms 1. ZRSR2 mutations are highly specific diagnostic markers for secondary AML and occur early in leukemogenesis, often persisting in clonal remission 2. These mutations belong to a distinct genetic subtype associated with worse clinical outcomes, including lower complete remission rates and decreased event-free survival 2. ZRSR2 mutations promote abnormal RNA splicing, generating recurrent mis-spliced mRNA isoforms that serve as actionable neoantigens for immunotherapy 3. ZRSR2-mutant clones grow significantly faster than certain other clones and contribute to clonal hematopoiesis of indeterminate potential 4. Additionally, ZRSR2 deficiency impairs DNA damage repair pathway activation and exhibits synthetic lethality with EXO1 loss, presenting a therapeutic vulnerability in DDR-deficient cancers 5.