ATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners

[
  "gene-mllt1",
  "gene-ell"
]

{
  "chronos_mean_kmt2a_rearranged": 0.0563,
  "chronos_mean_other_leukaemia": -0.0728,
  "difference": 0.1291,
  "pan_essentiality_all_lines": -0.0151,
  "selectivity_rank": 17301,
  "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": "FOUR ANNOTATED COMPARTMENTS, not one. UniProt Q13315 (fetched 2026-09-21) gives Nucleus (ECO:0000269), Cytoplasmic vesicle (ECO:0000269), Peroxisome matrix (ECO:0000269) and Cytoplasm/cytoskeleton/microtubule organizing center/centrosome (ECO:0000250, by similarity). Three of the four are experimental. This entry's argument - ATM phosphorylates three of the four KMT2A 3' partners - is entirely nuclear, and the peroxisomal and vesicular pools are functions an ATM inhibitor would also remove.",
  "subnuclear": "NUCLEOPLASM at baseline, with a MINORITY extraction-resistant pool in nuclear aggregates colocalising with gamma-H2AX and Nbs1 immediately after DSB induction [E_q71_loc1]. The damage compartment is a fraction of the total and is only visible after the nucleoplasmic majority has been washed away.",
  "explicit_no": "NOT MEASURED IN ANY KMT2A-REARRANGED CELL. UNPUBLISHED rather than not-applicable - ATM has an obvious subnuclear pool, nobody has looked in this disease. In particular, no experiment places ATM at a KMT2A fusion's chromatin, which the partner-phosphorylation argument in this entry would need.",
  "how_shown": "detergent extraction followed by immunofluorescence, with gamma-H2AX and Nbs1 colocalisation (PMID 11454856); UniProt Q13315 SUBCELLULAR LOCATION comment, fetched 2026-09-21",
  "systems": "human non-haematopoietic cells with induced DSBs; no KMT2A-rearranged system",
  "shown_for_fusion_localisation": "no - the substrate phosphorylation in this entry is biochemical and carries no compartment information",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "ATM (Q13315, 3056 aa) is NOT ATR (Q13535, 2644 aa). They are the two apical PIKKs of the damage response, they share the S/T-Q substrate motif this entry records, and the FANCI paper cited elsewhere in this tranche calls FANCI an 'ATM/ATR substrate' without separating them. Brief rule 66 also notes gene_exact:ATR returns SERPINA2 and ANTXR1 ahead of ATR, so the reverse lookup is unsafe too. Match on gene_primary and assert length.",
  "expressed_in": {
    "class": 1,
    "summary": "ubiquitous; ATM is expressed in all tissues. No lineage restriction."
  },
  "required_in": {
    "class": 2,
    "claim": "In MICE, Atm is required for T LYMPHOCYTE MATURATION and for gametogenesis; its absence also causes neurologic dysfunction and growth retardation [E_q71_ct1]. The haematopoietic cell type named is the developing T lymphocyte, not a stem or myeloid compartment, and the requirement is developmental rather than proliferative.",
    "pmids": [
      "8689683"
    ],
    "system_named_in_the_claim": "murine germline Atm knockout, normal development - no fusion present",
    "nodes": [
      "cell-type-early-t-precursor"
    ]
  },
  "NOT_A_DEPENDENCY_CATEGORY_ERROR": {
    "verdict": "ATM IS NOT A DEPENDENCY IN EITHER ARM AND THE SCAN'S RANK DOES NOT APPLY TO IT. Chronos mean is POSITIVE in the KMT2A-rearranged arm (+0.0563) and -0.0728 in other leukaemias; pan-essentiality across all lines is -0.0151, i.e. zero within noise. Rank 17,301 of 17,728 therefore does NOT mean 'strongly anti-selective dependency'; it means knocking ATM out gives a small GROWTH ADVANTAGE in the KMT2A-rearranged lines and essentially nothing in the others.",
    "why_this_matters": "This is the same category Q69 identified for CDKN2A in cycle 39: the scan ranks dependencies, and a tumour suppressor placed on a dependency scale produces a number that reads as a finding and is not one. ATM is a canonical tumour suppressor - biallelic loss causes ataxia-telangiectasia with lymphoid malignancy, and Atm-null mice get thymic lymphoma [E_q71_ct1]. Counting ATM among 'anti-selective' genes would be wrong.",
    "how_to_read_correction": "Read pan_essentiality_all_lines and both arm means FIRST. If both arms are positive, or the index arm is positive and pan-essentiality is zero within noise, the gene is not a dependency and the rank is meaningless for it."
  },
  "context": "murine germline knockout for the cell type; this project's DepMap scan for the (inapplicable) rank"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [],
    "claim": "NO CELL STATE IN THIS GRAPH'S VOCABULARY IS MAINTAINED BY ATM on published evidence. What Atm loss produces in mice is a developmental block in T lymphocyte maturation and a tumour-prone genome [E_q71_ct1] - a general genome-stability property of every cell, plus one lineage-restricted developmental requirement. Neither is a fusion-associated state.",
    "pmids": [
      "8689683"
    ],
    "system_named_in_the_claim": "murine germline Atm knockout"
  },
  "confidence": "strong",
  "caveats": "Murine germline knockout, human non-haematopoietic cells for the localisation, and a DepMap rank that does not apply because the gene is not a dependency. Nothing in this entry's cell-type or cell-state record is measured in a KMT2A-rearranged cell, and the entry's partner-phosphorylation argument is biochemical and carries no cell-type information at all.",
  "counter_evidence": {
    "note": "The one context where ATM-pathway loss demonstrably matters in a human haematopoietic compartment is replication-stress-driven HSPC attrition - and that is documented in Fanconi anaemia patients, where p53 is hyperactivated and HSPCs are lost through a p21-dependent arrest, in people with no fusion. The damage-response rationale in this disease is therefore available without KMT2A, and the direction of the intervention is the opposite of the one this entry's kinase-inhibitor framing implies.",
    "citation": {
      "title": "Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.",
      "authors": "Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, Regairaz M, Pla M, Vasquez N, Zhang QS, Pondarre C, Peffault de Latour R, Gluckman E, Cavazzana-Calvo M, Leblanc T, Larghero J, Grompe M, Socié G, D'Andrea AD, Soulier J",
      "year": 2012,
      "venue": "Cell Stem Cell",
      "pmid": "22683204",
      "doi": "10.1016/j.stem.2012.05.013",
      "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."
}