DNTT – Terminal Deoxynucleotidyl Transferase-negative Acute Lymphoblastic Leukemia

Terminal deoxynucleotidyl transferase (TdT), encoded by DNTT (HGNC:2983), is a DNA polymerase normally expressed in immature lymphocytes. Its absence has been noted in a rare subset of acute lymphoblastic leukemia (ALL), where TdT negativity helps distinguish early T-cell lineage cases from other lymphoid malignancies. A multi‑patient study reported 3 TdT‑negative ALL cases identified from a review of approximately 200 cases (PMID:10629138). This observation provides initial genetic evidence supporting the association between the DNTT gene and a distinct diagnostic subtype of ALL. Although familial segregation data are lacking, the consistency of immunophenotyping across independent cases underlines the potential clinical significance of this marker.

In addition to the case‑level evidence, another multi‑patient study identified DNTT among a panel of genes in ALL, emphasizing the relevance of related biomarkers in risk stratification (PMID:38814240). While the reported study primarily focused on interleukin‑15 mutations, the inclusion of DNTT highlights its utility when multiple markers are considered in diagnostic panels. However, no specific TGVS‑level variant in DNTT was reported, and the genetic evidence remains limited to immunophenotypic correlations rather than defined pathogenic mutations.

The genetic evidence, therefore, is modest, with the association resting on the identification of 3 unrelated TdT‑negative cases. Although this numeric observation is lower than required to reach the highest ClinGen scoring thresholds, the reproducibility of TdT negativity among a subset of ALL patients supports its relevance as a diagnostic signal. There is no clear segregation data in family studies, further underlining that the current evidence is based solely on case reports and multi‑patient retrospective analyses.

Substantial functional and experimental studies have been performed to elucidate the biological role of TdT. Multiple investigations have examined the regulation of the DNTT promoter, the effects of mutations on enzyme thermostability, and isoform‑specific catalytic activity. For instance, transcription assays have shown that the unique promoter structure of DNTT is critical for its lymphocyte‑restricted expression (PMID:8633066). Catalytic comparisons using murine isoforms reveal that a 20‑amino acid insertion affects thermosensitivity while preserving enzyme activity (PMID:10878023), and in vivo studies in transgenic mice have demonstrated isoform interactions that modulate TdT function (PMID:11136823). Additional engineering studies have successfully evolved thermostable variants and altered nucleotide incorporation biases (PMID:32497424; PMID:19502493; PMID:38915690).

No significant conflicting evidence has emerged that disputes the association between loss of TdT expression and the ALL subtype. While there is inherent heterogeneity in ALL, the reproducible demonstration of aberrant TdT levels coupled with detailed mechanistic insights from functional studies supports a biological role that reinforces its diagnostic utility. The absence of defined pathogenic variants of DNTT means that, at present, the evidence is predominantly anchored in expression patterns and functional assays.

In conclusion, while the genetic evidence linking DNTT to TdT‑negative ALL is limited due to the small number of reported cases and the absence of familial segregation data, the strong and multifaceted functional evidence underscores the gene’s biological role in lymphocyte development. This integrated evidence, despite its current limitations, supports the use of DNTT expression as a valuable diagnostic marker in acute lymphoblastic leukemia. Key take‑home sentence: Robust functional studies of DNTT provide essential biological context that, even in the setting of limited genetic case data, underscores its clinical utility in diagnosing a distinct ALL subtype.

References

• Archives of pathology & laboratory medicine • 2000 • Terminal deoxynucleotidyl transferase-negative acute lymphoblastic leukemia PMID:10629138
• Cellular and molecular biology (Noisy-le-Grand, France) • 2024 • IL-15 gene mutation as a molecular risk factor in acute lymphoid leukemia PMID:38814240
• Proceedings of the National Academy of Sciences of the United States of America • 1996 • Transcription of the lymphocyte-specific terminal deoxynucleotidyltransferase gene requires a specific core promoter structure PMID:8633066
• The Journal of biological chemistry • 2000 • Comparison of the two murine terminal deoxynucleotidyltransferase terminal isoforms PMID:10878023
• The Journal of experimental medicine • 2001 • The long isoform of terminal deoxynucleotidyl transferase enters the nucleus and, rather than catalyzing nontemplated nucleotide addition, modulates the catalytic activity of the short isoform PMID:11136823
• ACS synthetic biology • 2020 • Evolving a Thermostable Terminal Deoxynucleotidyl Transferase PMID:32497424
• Nucleic acids research • 2009 • Conferring a template-dependent polymerase activity to terminal deoxynucleotidyltransferase by mutations in the Loop1 region PMID:19502493
• bioRxiv : the preprint server for biology • 2024 • A massively parallel in vivo assay of TdT mutants yields variants with altered nucleotide insertion biases PMID:38915690

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