UBTF (upstream binding transcription factor) is a transcription factor that primarily functions to recognize ribosomal RNA gene promoters and activate transcription by RNA polymerase I through cooperative interactions with the SL1/TIF-IB complex. However, recent research has revealed that UBTF tandem duplications (UBTF-TD) represent a significant oncogenic driver in pediatric hematologic malignancies. UBTF-TD alterations occur in approximately 9% of relapsed pediatric acute myeloid leukemia (AML) cases and 4% of de novo pediatric AML 1. These duplications involve exon 13 and create a gain-of-function alteration that causes UBTF protein to mislocalize from ribosomal DNA loci to dysregulated genomic targets, including HOXA/HOXB gene clusters and MEIS1 2. UBTF-TD leukemias are characterized by poor chemotherapy response, normal karyotype or trisomy 8, and frequent co-occurring WT1 mutations or FLT3-ITD 1. The aberrant protein co-occupies genomic loci with KMT2A and menin, making these leukemias sensitive to menin inhibitors like SNDX-5613 2. UBTF alterations also occur in B-cell acute lymphoblastic leukemia through UBTF::ATXN7L3 fusions, which define a high-risk subtype associated with CDX2 deregulation 3. These findings establish UBTF alterations as important therapeutic targets in pediatric hematologic malignancies.