ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it

[
  "gene-atm",
  "gene-prkdc"
]

{
  "established_disease": "inhibition kills AML-MLL independently of p53, single-agent activity in vivo (E2); synergistic with MEK inhibition in Mll-Af4/N-Ras B-ALL (E3)",
  "during_transformation": "the ATR/ATM-CHK1/CHK2-p53/p21 checkpoint is a senescence barrier; inhibiting it ACCELERATED leukaemia development (E4)"
}

{
  "chronos_mean_kmt2a_rearranged": -1.0261,
  "chronos_mean_other_leukaemia": -1.1363,
  "difference": 0.1102,
  "pan_essentiality_all_lines": -1.1074,
  "selectivity_rank": 17082,
  "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": "NUCLEAR THROUGHOUT, with no cytoplasmic pool annotated. UniProt Q13535 fetched 2026-09-21 carries 'Nucleus' at ECO:0000269 on NINE references, 'Chromosome' at ECO:0000269 on one, and 'Nucleus envelope' at ECO:0000269 on three, plus an extensively coded note covering PML nuclear bodies, S-phase chromatin recruitment, damage- and hypoxia-induced foci, and relocalisation to the nuclear and micronuclear envelope. Every statement in the block carries an experimental code - no ECO:0000250 and no ECO:0000305 anywhere. Two of the nine nuclear references and the chromosome reference are NOT localisation studies [E_q77_loc5], but unusually for this tranche the founding localisation papers ARE cited [E_q77_loc1][E_q77_loc2].",
  "subnuclear": "FOUR SUBNUCLEAR ADDRESSES, ALL EXPERIMENTALLY CODED, AND THEY ARE CONDITION-DEPENDENT - ATR has the richest subnuclear record in this tranche. (1) CHROMATIN during S phase, in a paper whose title is exactly that claim [E_q77_loc2]. (2) DISCRETE NUCLEAR FOCI on DNA damage, hypoxia or replication-fork stalling. (3) PML NUCLEAR BODIES, depending on cell type - and the founding paper is an INTRANUCLEAR TRANSLOCATION study showing that ATR's own kinase activity regulates the redistribution of ATR and RPA after ionising radiation [E_q77_loc1]. (4) The NUCLEAR ENVELOPE, and separately the MICRONUCLEAR envelope, in response to mechanical stress and DNA damage [E_q77_loc3][E_q77_loc4]. The envelope pool is the one this graph has a live interest in: ATR phosphorylates LAMIN A/C and thereby induces nuclear-envelope rupture [E_q77_loc4], and this graph holds localization-nuclear-lamina-lads-kmt2a-r as an open lamina question in KMT2A-rearranged cells.",
  "how_shown": "immunofluorescence of intranuclear ATR and RPA redistribution after ionising radiation, with kinase-dead ATR as the control [E_q77_loc1]; chromatin fractionation across the cell cycle [E_q77_loc2]; live imaging and mechanical perturbation for the nuclear-envelope checkpoint [E_q77_loc3]; lamin A/C phosphoproteomics plus envelope-rupture imaging [E_q77_loc4]; and, for the oldest annotation, immunocytology of meiotic chromosome spreads [E_q77_loc6]",
  "systems": "human cultured cells for most of it; MOUSE MEIOTIC SPERMATOCYTES for the 1996 founding chromosome-association result; migrating and mechanically confined cells for the envelope work. NO haematopoietic localisation system and nothing KMT2A-rearranged - which is notable given that this entry already holds the strongest preclinical therapeutic case in the break-repair beat.",
  "shown_for_fusion_localisation": "NO for ATR's OWN localisation - nobody has imaged or fractionated ATR in a KMT2A-rearranged cell, an MLL-ENL mouse or an Mll-Af4 model, despite two published in vivo therapeutic studies in exactly those systems. BUT THE ATR PATHWAY HAS BEEN USED AS A LOCALISATION INSTRUMENT ON THIS GRAPH'S CENTRAL PROTEIN, WHICH IS THE MORE INTERESTING ANSWER: menin's chromatin-bound pool rises 2.8-fold after UV in an ATR-CHK1-dependent manner [E_q77_loc7]. That is a fusion-adjacent spatial result in which ATR is the upstream regulator rather than the object.",
  "node": "localization-nuclear-lamina-lads-kmt2a-r",
  "the_menin_connection_is_the_reason_this_block_matters": "Cycle 42's king log named a cheap untested prediction: if menin's chromatin pool is damage-regulated, DNA-damaging chemotherapy should move menin onto chromatin, and every patient in the pivotal menin-inhibitor trials received cytotoxics. THE UPSTREAM KINASE IN THAT PREDICTION IS ATR, AND THIS IS ITS ENTRY. Farley et al. fractionated HEK293 cells into soluble, two chromatin and nuclear-matrix compartments, found menin in chromatin peaking at 4 h post-UV with a 2.8-fold dose-dependent maximum, and blocked it with caffeine and probed it with full-length and truncated-active CHK1 constructs [E_q77_loc7]. So a menin subnuclear readout - the third pharmacodynamic instrument the king log says does not exist - already has a published protocol and a published ATR-dependent stimulus. The unattempted experiment is that fractionation in a KMT2A-rearranged blast, with and without a menin inhibitor, with and without an ATR inhibitor."
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "ATR is Q13535, 2,644 aa. data/symbol-collisions.json was grepped BEFORE the first query and THE ROW ALREADY EXISTED: token ATR, class query_returns_the_wrong_gene_first, note 'gene_exact:ATR returns SERPINA2 and ANTXR1 ahead of ATR'. RE-VERIFIED LIVE on 2026-09-21 and it still fires in exactly that order - P20848 SERPINA2 (421 aa) first, Q9H6X2 ANTXR1 (564 aa) second, Q13535 ATR (2,644 aa) third. The registry row carried 'verified: earlier cycle, not re-verified 2026-09-20'; this beat re-verified it. The registry file was NOT edited, per the dispatch - the re-verification is recorded here and in the memo.",
  "expressed_in": {
    "class": 1,
    "summary": "ubiquitous and DepMap pan-essential - pan_essentiality_all_lines -1.1074 in this entry's own scan block, with the KMT2A-rearranged arm slightly LESS dependent than other leukaemia lines (difference +0.1102). Per brief rule 84 the selectivity rank (17,082 of 17,728) is reported as a rank and not as membership of the anti-selective half, which is a base rate."
  },
  "required_in": {
    "class": 2,
    "claim": "IN ADULT MICE, DELETING ATR CAUSES ACUTE LOSS OF TISSUE-SPECIFIC STEM AND PROGENITOR CELLS IN EXACTLY THE TISSUES THAT DEPEND ON CONTINUOUS PROLIFERATION - including THYMIC INVOLUTION - together with hair greying, alopecia, kyphosis, osteoporosis and fibrosis, and exhaustion of tissue renewal and homeostatic capacity [E_q77_ct1]. This is the cell-type statement that the DepMap pan-essentiality number gestures at and cannot make: the requirement is in the STEM AND PROGENITOR compartment of renewing tissues, which is precisely the compartment an infant patient cannot afford to lose.",
    "pmids": [
      "18371340"
    ],
    "system_named_in_the_claim": "conditional ATR deletion in adult mice, normal tissues - no leukaemia and no fusion",
    "nodes": [
      "cell-type-hsc-bone-marrow"
    ],
    "how_this_bears_on_the_therapeutic_case": "This entry's bite_back already names the senescence-barrier problem - inhibiting the ATR/ATM-CHK1/CHK2-p53/p21 checkpoint ACCELERATED leukaemia development in the MLL-ENL-ER mouse. The Ruzankina result is a SECOND and independent normal-tissue cost, and it is of a different kind: not a lost tumour-suppressive barrier, but acute stem- and progenitor-cell attrition with a premature-ageing phenotype. In a child expected to live seventy years, a drug whose murine germline-equivalent phenotype is premature ageing deserves that sentence written down in the cell-type block and not only in a toxicity list."
  },
  "context": "murine adult normal tissues; no human material and no fusion"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-replication-stress-icl-repair",
      "cell-state-quiescence"
    ],
    "claim": "ATR IS THE SENSOR THAT DEFINES THE REPLICATION-STRESS STATE THIS GRAPH TRACKS, and in this disease the same sensor sets a second state at a different stage. The replication-stress arm is definitional: ATR is recruited to CHROMATIN during S phase [E_q77_loc2], redistributes into discrete nuclear foci on fork stalling and hypoxia, and its inhibition produces chromosomal breakage and death in MLL-ENL AML cells independently of p53 [E2]. The second arm is the senescence barrier this entry already records at [E4]: oncogene activation in a regulatable MLL-ENL-ER mouse engages the ATR/ATM-CHK1/CHK2-p53/p21 checkpoint and CELLULAR SENESCENCE, and inhibiting that barrier accelerated the transition to immature cell states. Same kinase, opposite therapeutic sign, separated only by stage.",
    "pmids": [
      "14871897",
      "22516260"
    ],
    "system_named_in_the_claim": "human cultured cells for the chromatin-recruitment mechanism; a murine regulatable MLL-ENL-ER model for the senescence barrier; murine AML(MLL) allografts for the vulnerability"
  },
  "the_third_state_nobody_has_named": "Farley et al. show that MENIN's partition between soluble, chromatin and nuclear-matrix fractions is itself an ATR-CHK1-regulated variable after UV [E_q77_loc7]. If that holds in a blast, then 'under DNA damage' is a distinct chromatin state of the menin-KMT2A axis, and every pivotal menin-inhibitor trial ran in patients who had received cytotoxic therapy. This graph has no cell-state entry for it and the prediction is testable in a fractionation.",
  "confidence": "strong",
  "caveats": "The stem-cell-loss result is murine, in normal adult tissues, with germline-conditional deletion rather than pharmacological inhibition - a drug gives partial, reversible occupancy, which is the scope objection this graph's database-facts rule insists on. The senescence-barrier result is a regulatable murine MLL-ENL-ER system, not human and not the index fusion. Both published KMT2A-rearranged ATR results carry an activating RAS lesion in the model, which this entry's open questions already flag. And the menin fractionation is HEK293 cells with UV, a system three steps from an infant blast.",
  "counter_evidence": [
    {
      "note": "The direction of the ATR requirement inverts between stages and the entry must not be allowed to settle on one. Against the therapeutic reading: in the MLL-ENL-ER mouse the ATR/ATM-CHK1/CHK2-p53/p21 checkpoint is a FAIL-SAFE ANTI-CANCER BARRIER whose experimental inhibition ACCELERATED acquisition of immature, stem-like states and acute leukaemia. Against the barrier reading: in established AML(MLL) disease, ATR inhibition kills independently of p53 with single-agent in vivo activity. A child with KMT2A-rearranged leukaemia has both populations at once - established blasts and normal progenitors in which the barrier is what prevents a second transformation - so the two results are not sequential in the patient the way they are in the models.",
      "citation": {
        "title": "Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.",
        "authors": "Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ",
        "year": 2007,
        "venue": "Cell Stem Cell",
        "pmid": "18371340",
        "doi": "10.1016/j.stem.2007.03.002",
        "type": "paper"
      }
    }
  ]
}