DNTT (DNA nucleotidylexotransferase), also known as terminal deoxynucleotidyl transferase (TdT), is a template-independent DNA polymerase that catalyzes random addition of deoxynucleoside triphosphates to DNA 3' ends [UniProt]. During B and T cell development, DNTT adds nucleotides at junctions of rearranged immunoglobulin and T-cell receptor gene segments, generating N-region diversity critical for immune repertoire [UniProt]. DNTT participates in DNA damage repair via nonhomologous end joining [GO annotations]. Clinically, DNTT expression inversely correlates with therapeutic resistance in acute lymphoblastic leukemia (ALL). Loss of DNTT expression drives resistance to inotuzumab ozogamicin (InO), an antibody-calicheamicin conjugate for B-ALL, by attenuating InO-induced DNA damage response and mitochondrial apoptotic priming 1. Genome-wide CRISPR screening and retrospective patient analysis confirmed DNTT downregulation as a primary resistance mechanism 2. Conversely, high DNTT expression characterizes ALL blasts and associates with improved outcomes 3. In acute myeloid leukemia, DNTT-mediated mutagenesis of gene length mutations correlates with better prognosis in allogeneic hematopoietic stem cell transplantation recipients 4. DNTT represents a potential biomarker for individualizing leukemia therapy and predicting treatment response.