LUC7L2 is a pre-mRNA splicing factor that functions as a U1 snRNP-associated protein involved in 5' splice site recognition and selection 1. The protein binds RNA through its arginine-serine-rich domain and preferentially enhances splicing of "right-handed" 5' splice sites with stronger consensus sequences on the intron side 2. Mechanistically, LUC7L2 regulates alternative splicing of multiple genes involved in cellular metabolism, including the glycolytic enzyme PFKM and the cystine/glutamate antiporter SLC7A11, thereby repressing oxidative phosphorylation and promoting glycolysis 3. LUC7L2 also mediates intron retention of MLH1, a mismatch repair gene, which can be upregulated via histone H3K9 lactylation to confer temozolomide resistance in glioblastoma 4. Loss or mutation of LUC7L2 is clinically significant in myeloid malignancies, where it functions as a haploinsufficient tumor suppressor gene on chromosome 7 5. Recurrent LUC7L2 mutations and deletions are identified in myelodysplastic syndromes and acute myeloid leukemia 6. The gene also shows selective essentiality in chordoma 7. LUC7L2's dysregulation contributes to aberrant splicing networks in hematologic malignancies 8.