DNTT (TdT) - a real gene the graph calls by its enzyme nickname, and TdT-negativity is 100% KMT2A-rearranged in the largest paediatric series

[
  "TDT"
]

[
  "TDT",
  "TdT"
]

[]

{
  "tdt_negative_b_all_n": 21,
  "kmt2a_rearranged_pct": 100,
  "tdt_positive_n": 896,
  "kmt2a_rearranged_pct_tdt_positive": 1.9,
  "median_age_years": 1.4,
  "wbc_x10e9": 52.8,
  "efs_5yr_pct": 76.2,
  "efs_5yr_pct_tdt_positive": 90.3,
  "partner_association": "MLLT1 (P = 0.026)",
  "ng2_missed_cases_that_are_tdt_negative_pct": 63,
  "pmid": "34148065",
  "title": "Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia.",
  "authors": "Klairmont MM, Zhou Y, Cheng C, et al.",
  "venue": "Mod Pathol",
  "year": 2021,
  "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}

{
  "graph_mentions_TdT": 14,
  "graph_mentions_DNTT": 4,
  "ratio": 3.5,
  "pubmed_spelled_out_AND_kmt2a": 39,
  "pubmed_DNTT_AND_kmt2a": 2,
  "measured": "2026-09-20"
}

{
  "chronos_mean_kmt2a_rearranged": -0.0375,
  "chronos_mean_other_leukaemia": -0.0342,
  "difference": -0.0034,
  "pan_essentiality_all_lines": -0.0459,
  "selectivity_rank": 8723,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}

{
  "subcellular": "NUCLEUS, the only location UniProt P04053 annotates, at ECO:0000269 (fetched 2026-09-21), with Nucleus as its sole cellular-component keyword. This is consistent with the free-text note already in this entry's data.localisation field, which Q71 has left untouched; the structured field is added because check-pi-dimensions.py reads localization, subcellular_localization and subnuclear_localization and does not read the British spelling.",
  "subnuclear": "NOT MEASURED. No subnuclear compartment has been published for TdT in any system. The natural place to look would be at RAG-generated breaks during V(D)J recombination, since that is where the enzyme acts [E_q71_ct1], and nobody has imaged it there.",
  "explicit_no": "UNPUBLISHED, not not-applicable. TdT is a 509-residue nuclear polymerase acting at a defined chromosomal reaction and a subnuclear pool is a reasonable expectation. Nothing at all has been measured in a KMT2A-rearranged cell - which is notable, because the clinically informative fact about this gene in this disease is that its PROTEIN IS ABSENT from the blasts, and nobody has asked whether the residual protein in partially-positive cases is differently distributed.",
  "not_a_surface_antigen": "Restating what this entry already says, because it is a localisation point: DNTT is nuclear and is NOT a surface antigen. It sits in this beat only because it is measured on the same diagnostic flow panel as the surface markers - which requires permeabilisation, a methodological difference that a panel readout hides.",
  "how_shown": "UniProt P04053 SUBCELLULAR LOCATION comment at ECO:0000269, fetched 2026-09-21; function at V(D)J junctions from the murine knockout (PMID 8356452)",
  "systems": "murine normal lymphocyte development; no KMT2A-rearranged localisation measurement",
  "shown_for_fusion_localisation": "no",
  "node": "localization-plasma-membrane-leukaemic-surface-antigens"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "DNTT (P04053, 509 aa, 'DNA nucleotidylexotransferase', UniProt gene synonym TDT) is the gene; TdT is the enzyme nickname the clinical literature and this graph mostly use. Brief rule 69 measured the consequence: TdT appears in 14 entries of this graph and DNTT in 4, so any token-counting or absence check keyed to the HGNC symbol under-counts this gene roughly fourfold. Both papers cited here are titled with the enzyme name or the abbreviation, not the symbol.",
  "expressed_in": {
    "class": 1,
    "summary": "IMMATURE LYMPHOID PRECURSORS, and developmentally timed. TdT acts during V(D)J rearrangement of lymphocyte receptor genes in both lineages, and in mice the gene SWITCHES ON DURING THE FIRST WEEK AFTER BIRTH [E_q71_ct1]. This is the most stage-restricted expression pattern in this tranche and it is the basis of TdT's use as a lymphoblast marker.",
    "nodes": [
      "cell-type-pro-b",
      "cell-type-pre-b",
      "cell-type-early-t-precursor"
    ]
  },
  "required_in": {
    "class": 2,
    "claim": "In MICE, TdT is required for N-nucleotide addition and hence for the adult lymphocyte receptor repertoire's junctional diversity, and its absence lets homology-directed recombination dominate the junctions [E_q71_ct1]. It is required for REPERTOIRE, not for cell survival: TdT-null mice are described as mature animals with an immature repertoire.",
    "pmids": [
      "8356452"
    ],
    "system_named_in_the_claim": "murine germline TdT mutant, normal lymphocyte development - no fusion present"
  },
  "not_required_in": {
    "claim": "NOT A DEPENDENCY ANYWHERE. Chronos -0.0375 in the KMT2A-rearranged arm against -0.0342 in other leukaemias, difference -0.0034, pan-essentiality -0.0459, rank 8,723 of 17,728. Every number is within noise of zero. Rank 8,723 falls nominally in the selective half - the midpoint is 8,864 - and that is meaningless: this is a NON-DEPENDENCY, and its rank is set by which side of zero a 0.003 difference happens to land on.",
    "why_this_is_worth_stating": "It is the clearest demonstration in this tranche that a rank near the middle of the scan carries no information. The same discipline that refuses to call SIRT1 anti-selective refuses to call DNTT selective."
  },
  "context": "murine normal lymphocyte development; the St Jude TdT-negative series for the disease association; this project's DepMap scan for the (non-)dependency"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-neonatal-window-of-transformability"
    ],
    "claim": "In MICE, the TdT gene SWITCHES ON DURING THE FIRST WEEK AFTER BIRTH, and that switch-on is what expands lymphocyte receptor diversity beyond the fetal repertoire [E_q71_ct1]. TdT does not MAINTAIN a state; it MARKS a developmental transition, and it marks the same perinatal transition this graph's neonatal-window entry is about. A fetal or neonatal lymphoid progenitor is TdT-low by developmental schedule, before any leukaemia exists.",
    "pmids": [
      "8356452"
    ],
    "system_named_in_the_claim": "murine normal perinatal lymphocyte development - no fusion present",
    "evidence_class_warning": "This is a class-1 EXPRESSION-TIMING observation being used to illuminate a state, not a class-3 maintenance result. It is labelled here rather than promoted, per the three-evidence-class discipline.",
    "and_it_bears_directly_on_the_disease_observation": "TdT-negative B-ALL is 100% KMT2A-rearranged and has a median age of 1.4 years [counter-evidence on E_q71_ct1]. A perinatal-onset leukaemia arising from a progenitor that has not yet switched TdT on would look exactly like that WITHOUT the fusion having to repress anything. That is a developmental-timing explanation for a marker phenotype currently read as a fusion property, and nothing in the cited series distinguishes the two."
  },
  "confidence": "moderate",
  "caveats": "The perinatal switch-on is MURINE and the human timing is not established by that paper. The TdT-negative series is human and clinical but is an association, not a mechanism, and the authors themselves say the high-risk features are secondary to the KMT2A rearrangement rather than to TdT status. The developmental-timing alternative offered above is a hypothesis this beat is raising, not a published finding, and it is marked as such. Confidence is moderate for that reason.",
  "counter_evidence": {
    "note": "The straightforward alternative reading of TdT-negativity is a technical and a partner one rather than a developmental one. In the St Jude series TdT-negativity within KMT2A-rearranged B-ALL was significantly associated with the MLLT1 partner (P = 0.026) and was NOT independently predictive of survival - so it tracks with a specific rearrangement rather than behaving as an independent biological axis, and 63% of cases the NG2 marker misses are TdT-negative, which makes the observation partly a property of the diagnostic panel. Any developmental-timing hypothesis has to explain the partner association.",
    "citation": {
      "title": "Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia.",
      "authors": "Klairmont MM, Zhou Y, Cheng C, Pui CH, Jeha S, Gruber TA, Liu Y, Inaba H, Choi JK",
      "year": 2021,
      "venue": "Mod Pathol",
      "pmid": "34148065",
      "doi": "10.1038/s41379-021-00853-3",
      "type": "paper"
    }
  }
}

{
  "open_targets_dataversion": "26.06",
  "note": "Added by Q71 per brief rule 83; Open Targets dataVersion fetched live 2026-09-21 as year 26 month 06. Scan denominator for this gene: n_all_lines 1208."
}