The curious incident of TdT-mediated mutations in AML

Abstract

In this issue of Blood, Borrow et al reanalyze published DNA sequencing data and report, in back-to-back papers,1,2 that the lymphoid enzyme terminal deoxynucleotide transferase (TdT) appears to be involved in the causation of the 2 most common types of gene mutation in human acute myeloid leukemia (AML),3 namely internal tandem duplications of FLT3 (FLT3-ITD) and short insertions/duplications within the final exon of NPM1 (NPM1c). The normal function of TdT is to increase the diversity of the immunoglobulin and T-cell receptor (TCR) loci, by adding nontemplated nucleotides to their variable regions. Other enzymes involved in generating this diversity, such as RAG and AID, can act illegitimately to cause oncogenic mutations in acute lymphoblastic leukemia (ALL).4 Here, the work by Borrow et al proposes TdT as a major mutagen in AML, an unexpected finding that forces a reevaluation of our understanding of myeloid leukemogenesis.