CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument

[
  {
    "combination": "chidamide + MI-3 (tool menin inhibitor)",
    "disease": "MLL-r AML",
    "localisation": "CHK1/CHK2, explicitly NOT ATR/ATM",
    "repair_arm": "homologous recombination, not NHEJ",
    "pmid": "31590682",
    "title": "Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair.",
    "authors": "Ye J, Zha J, Shi Y, et al.",
    "venue": "Clin Epigenetics",
    "year": 2019,
    "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."
  },
  {
    "combination": "chidamide + (+)-JQ-1 (BET inhibitor)",
    "disease": "MLL-r AML lines",
    "localisation": "whole axis: p-ATR, p-CHK1, p-ATM, p-CHK2 all reduced",
    "repair_arm": "RAD51 and 53BP1 both reduced",
    "pmid": "39479812",
    "title": "[Chidamide Combined with (+) -JQ-1 to Kill MLL-Rearrangement Acute Myeloid Leukemia Cells by Disrupting the DNA Damage Response Pathway].",
    "authors": "Zhang Q, Li FM, Wang W, et al.",
    "venue": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
    "year": 2024,
    "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."
  }
]

{
  "chronos_mean_kmt2a_rearranged": -1.7613,
  "chronos_mean_other_leukaemia": -1.85,
  "difference": 0.0887,
  "pan_essentiality_all_lines": -1.7664,
  "selectivity_rank": 16624,
  "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, CHROMOSOME, CYTOPLASM AND CENTROSOME - all four experimentally coded. UniProt O14757 fetched 2026-09-21 carries 'Nucleus' at ECO:0000269 on five references, 'Chromosome' on three, 'Cytoplasm' on one and 'Cytoplasm, cytoskeleton, microtubule organizing center, centrosome' on one, plus a fully coded note covering XPO1/CRM1-mediated nuclear export, the interphase centrosomal pool and SPRTN-mediated removal from chromatin. No ECO:0000250 and no ECO:0000305 anywhere. Unlike most records in this tranche, the cited papers ARE largely about CHK1's compartment - rule 91 passes here more often than it fails.",
  "subnuclear": "CHROMATIN, AND A CENTROSOMAL POOL OUTSIDE THE NUCLEUS ALTOGETHER - CHK1 is the entry in this tranche where the compartment IS the regulation, in three independent registers. (1) CHROMATIN: CHK1 associates with chromatin, and the association is coupled to Ser-345 phosphorylation and 14-3-3 binding; removal from chromatin is executed by PROTEOLYTIC CLEAVAGE of the CHK1 C-terminus by the SPRTN protease [E_q77_loc2][E_q77_loc4]. (2) NUCLEAR EXPORT is mediated at least in part by XPO1/CRM1 [E_q77_loc2] - the same exportin this graph already tracks for CALM-AF10 and for XPO1's own chromatin-versus-soluble pool. (3) CENTROSOME, specifically during INTERPHASE, where centrosome-associated CHK1 prevents premature activation of cyclin-B-CDK1 [E_q77_loc3]. That third pool is not subnuclear at all and is the reason this entry does not answer the subnuclear question with one word.",
  "how_shown": "chromatin fractionation with phospho-Ser345 and 14-3-3 readouts, plus leptomycin-B-type export analysis [E_q77_loc2]; immunofluorescence of centrosome-associated CHK1 across the cell cycle with cyclin-B-CDK1 activation as the functional readout [E_q77_loc3]; SPRTN-dependent C-terminal cleavage and chromatin-removal assays [E_q77_loc4]; and, for the disease-relevant case, cytoplasmic CHK1 accumulation in PTEN-null cells and in primary PTEN-negative carcinomas [E_q77_loc5]",
  "systems": "human and murine cultured cells throughout; primary breast carcinomas for the PTEN result. NO haematopoietic localisation system, no primary blast, nothing KMT2A-rearranged - which matters because this entry's whole reason for existing is two combination results in KMT2A-rearranged AML lines, neither of which measured where CHK1 is.",
  "shown_for_fusion_localisation": "NO for CHK1 itself - nobody has measured CHK1's localisation in a KMT2A-rearranged cell, in either of the two chidamide combination studies this entry is built on or anywhere else. PARTIAL in the indirect sense: CHK1 is, with ATR, the documented upstream regulator of MENIN's chromatin-bound pool - menin in the chromatin fraction rises 2.8-fold at 4 h post-UV, caffeine blocks it, and the pathway was probed with full-length and truncated-active CHK1 constructs [E_q77_loc6].",
  "node": "localization-xpo1-chromatin-bound-versus-soluble-pool",
  "the_crm1_cross_link_nobody_has_drawn": "CHK1's nuclear export is XPO1/CRM1-mediated. This graph holds three separate CRM1 stories - the CALM-AF10 nuclear export signal that is necessary and sufficient for transformation, XPO1's own chromatin-versus-soluble pool, and the SET-NUP214 CRM1 nuclear bodies - and none of them mentions CHK1. The prediction is immediate and untested: an XPO1 inhibitor should TRAP CHK1 IN THE NUCLEUS, which is the opposite of what an HDAC-inhibitor combination does to it. Selinexor and a CHK1-lowering combination given together would be pushing the same protein in opposite directions, and nobody has looked.",
  "the_compartment_is_the_mechanism_precedent": "The PTEN result is the cleanest published case of CHK1's compartment carrying a disease phenotype, and it is a compartment change with a named chemistry: AKT phosphorylates CHK1 at Ser-280, the phosphorylated protein is mono- or di-ubiquitylated and accumulates in the CYTOPLASM, a S280A mutant restores the checkpoint, and primary PTEN-negative carcinomas with high phospho-AKT show increased cytoplasmic CHK1 and aneuploidy [E_q77_loc5]. PTEN and the PI3K/AKT axis are live in KMT2A-rearranged leukaemia, and no one has asked whether CHK1 is mislocalised in these blasts."
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "CHEK1 is O14757, 476 aa, primary gene name CHEK1, synonym CHK1; the paralogue CHEK2 is O96017 at 543 aa. data/symbol-collisions.json was grepped for CHEK1 and CHK1 before the first query and has NO row for either; none is proposed, because gene_exact:CHEK1 returns exactly one reviewed row. The live hazard for this gene is RETRIEVAL rather than resolution and this entry already records it: (MLL OR KMT2A) AND CHEK1 returns 1 record while (MLL OR KMT2A) AND CHK1 returns 5, a fivefold undercount from using the HGNC symbol - the same shape as the SEPT9/SEPTIN9 rule. Every query in this beat used both spellings.",
  "expressed_in": {
    "class": 1,
    "summary": "broadly expressed and DepMap PAN-ESSENTIAL - pan_essentiality_all_lines -1.7664 in this entry's own scan block, the deepest in this tranche, with the KMT2A-rearranged arm marginally LESS dependent than other leukaemia lines (difference +0.0887). Per brief rule 84 the rank (16,624 of 17,728) is reported as a rank, not as membership of a half of the distribution."
  },
  "required_in": {
    "class": 2,
    "claim": "IN HUMAN T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA, CHK1 IS OVEREXPRESSED AND HYPERACTIVATED AND IS REQUIRED - and the therapeutic-window result is the part worth carrying. CHEK1 mRNA is highly abundant in the PROLIFERATIVE T-ALL subgroup; the cells carry constitutively elevated phospho-RPA32 and gamma-H2AX, i.e. standing replication stress; PF-004777736 or shRNA silencing impairs proliferation and viability, causing accumulation of incompletely replicated DNA, ATM/CHK2 activation and ATM- and caspase-3-dependent apoptosis; CHK1 inhibition delays in vivo growth of T-ALL xenografts; AND, CRUCIALLY, PRIMARY T-ALL CELLS ARE SENSITIVE AT THERAPEUTIC DOSES WHILE NORMAL THYMOCYTES ARE NOT, even with stromal or IL-7 survival support [E_q77_ct1].",
    "pmids": [
      "25132270"
    ],
    "system_named_in_the_claim": "human primary T-ALL cells, T-ALL lines and xenografts, with normal human thymocytes as the comparator - a lymphoid leukaemia, but NOT KMT2A-rearranged and NOT B-lineage",
    "nodes": [
      "cell-type-early-t-precursor"
    ],
    "why_this_matters_to_the_bite_back": "This entry's central warning is that the chidamide combinations work by impairing homologous recombination in a child who faces years of genotoxic therapy. The T-ALL result is the best published counterweight AND it does not dissolve the warning: it shows a real normal-versus-leukaemic window for CHK1 inhibition in a lymphoid leukaemia, measured against primary normal thymocytes rather than against a cell line. A window in proliferation is not a window in genomic instability, and the second-malignancy argument is about the latter."
  },
  "context": "human T-ALL primary cells and xenografts; no KMT2A-rearranged material"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-replication-stress-icl-repair",
      "cell-state-unsynchronisable-cell-cycle"
    ],
    "claim": "CHK1 IS WHAT MAKES A HIGH-REPLICATION-STRESS STATE SURVIVABLE, which is a different claim from causing it. In human T-ALL the cells carry constitutive phospho-RPA32 and gamma-H2AX and are addicted to CHK1 to tolerate it; removing CHK1 does not relieve the stress, it converts it into incompletely replicated DNA, ATM/CHK2 activation and apoptosis [E_q77_ct1]. The cell-cycle half of the state is enforced from an unexpected compartment: CENTROSOME-associated CHK1 prevents premature activation of cyclin-B-CDK1 during interphase [E_q77_loc3], so the mitotic-entry timer this graph tracks is set by a cytoplasmic pool of a nuclear checkpoint kinase.",
    "pmids": [
      "25132270",
      "15311285"
    ],
    "system_named_in_the_claim": "human primary T-ALL and xenografts for the replication-stress state; human cultured cells for the centrosomal timer - no fusion in either"
  },
  "the_state_this_predicts_for_kmt2a_r_and_nobody_has_measured": "If CHK1 dependence tracks standing replication stress rather than lineage, the question for this disease is whether infant KMT2A-rearranged blasts carry the phospho-RPA32/gamma-H2AX signature that predicted CHK1 addiction in T-ALL. That is two antibodies on existing material. This graph's own DepMap arm says KMT2A-rearranged lines are marginally LESS CHK1-dependent than other leukaemia lines, which argues they may not - and if so, the chidamide combinations are not working through a pre-existing CHK1 addiction but by creating a dependency, which is a different therapeutic logic with a different resistance profile.",
  "confidence": "moderate",
  "caveats": "The requirement and state evidence is T-LINEAGE, not B-lineage, and carries no KMT2A rearrangement. The centrosomal-timer result is in adherent cultured cells. Both combination results this entry is built on measure PHOSPHORYLATION of CHK1, not its amount or its location, so nothing in the KMT2A-rearranged literature constrains the compartment claims here at all. And the PTEN mechanism, which is the one published route to mislocalising CHK1 in a cancer, was established in breast carcinoma.",
  "counter_evidence": [
    {
      "note": "The two published KMT2A-rearranged combination results DISAGREE about where in the axis the effect lands, and this entry already says so: Ye et al. place it at CHK1 and CHK2 and explicitly NOT at ATR and ATM, while Zhang et al. report p-ATR, p-CHK1, p-ATM and p-CHK2 all falling together. Adding a compartment layer makes the discriminating experiment more valuable, not less: an ATR inhibitor and a CHK1 inhibitor with the same HDAC inhibitor in the same lines, read out by chromatin fractionation rather than by whole-cell phospho-blot, would say whether the combination removes CHK1 activity or removes CHK1 from chromatin. Those are different mechanisms with different resistance routes and the existing data cannot separate them.",
      "citation": {
        "title": "SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.",
        "authors": "Halder S, Torrecilla I, Burkhalter MD, Popović M, Fielden J, Vaz B, Oehler J, Pilger D, Lessel D, Wiseman K, Singh AN, Vendrell I, Fischer R, Philipp M, Ramadan K",
        "year": 2019,
        "venue": "Nat Commun",
        "pmid": "31316063",
        "doi": "10.1038/s41467-019-11095-y",
        "type": "paper"
      }
    }
  ]
}