GenemoderateQ43-break-repair-machinery

CHEK2 (CHK2) - named in every combination mechanism here and measured on its own in none of them

also called CHEK2 · CHK2 · CDS1 · RAD53 · checkpoint kinase 2 · serine/threonine-protein kinase Chk2

CHK2 is the checkpoint switch downstream of the break-sensing alarm ATM, the partner of CHK1. Every drug combination in this graph that claims to work by breaking the checkpoint lists CHK2 alongside CHK1 - and not one of them tested CHK2 by itself.

The same thing, for a scientist

CHEK2 (O96017, 543 aa) is the ATM-effector checkpoint kinase, paralogue of the ATR-effector CHEK1. This entry exists to state something uncomfortable: **CHK2 appears in the mechanism sentence of every KMT2A-rearranged combination result in this graph and has never been perturbed alone in any of them.** Chidamide plus MI-3 disrupts the checkpoint 'at the level of CHK1 and CHK2 kinases' [E2]; chidamide plus JQ1 reduces p-CHK1 and p-CHK2 together [E3]; the MLL-ENL senescence barrier is described as an 'ATR/ATM-Chk1/Chk2-p53/p21 checkpoint' [E4]. In each case CHK2 is named as part of a pair or a chain, never measured as a separable node. A phospho-western showing p-CHK2 down alongside p-CHK1 is consistent with CHK2 mattering, with CHK2 being a passenger of ATM inhibition, and with the two kinases being read as one axis - and the published data do not distinguish these. `(MLL OR KMT2A) AND CHEK2` returns **2** PubMed records and title-checking finds **neither** is about this disease [E5]. So the honest position is: CHK2 is a named participant with no member-level measurement, in a family where this graph has repeatedly found that naming is not measurement.

Go deeper

The pair problem, stated as a rule rather than a complaint

CHK1 and CHK2 are a paralogue pair that sit on different branches - CHK1 under ATR and replication stress, CHK2 under ATM and double-strand breaks. That makes them the opposite of interchangeable, and it makes 'CHK1/CHK2' as a compound noun actively misleading when it appears in a mechanism claim.

Three tests would separate them and none has been run in a KMT2A-rearranged system: a selective CHK2 inhibitor or CHEK2 knockout with the same HDAC partner; an ATM inhibitor as a substitute (which should reproduce a CHK2-dependent effect and not a CHK1-dependent one); and epistasis with the fusion itself. Until one of them exists, any sentence in this graph naming CHK2 as a mechanism in this disease should be read as naming.

The one CHK2 fact that is disease-relevant and is not about KMT2A

CHEK2 is a well-established germline cancer-predisposition gene, and germline CHEK2 variants appear in paediatric leukaemia predisposition panels. This entry makes no claim about that in KMT2A-rearranged disease because the searched literature contains none: the two PubMed records returned by (MLL OR KMT2A) AND CHEK2 are a bovine cumulus-cell study and a follicular thyroid cancer sequencing paper 5. Recording that absence with its query is more useful than a plausible sentence about predisposition that no study in this disease supports.

Facts and figures

uniprot	O96017
length AA	543
gene symbol	CHEK2
accession resolution	gene_exact:CHEK2 AND organism_id:9606 AND reviewed:true returned exactly 1 row; gene_primary CHEK2, length 543. Paralogue control O14757 / CHEK1 / 476 aa resolved in the same call.
paralogue	gene-chek1
upstream kinase	gene-atm
measurement status	NAMED IN THREE KEY RESULTS, MEASURED SEPARATELY IN NONE. No CHEK2 knockdown, knockout or selective inhibitor has been used in a KMT2A-rearranged system in the literature searched here.
subnuclear localization	TWO CONDITIONAL ADDRESSES AND NO CONSTITUTIVE ONE. (1) PML nuclear bodies / DNA-SCARS, damage-dependent, and CHK2's documented role there is as much a REGULATOR of body number as a resident - PML-body fission after double-strand breaks requires Chk2 (PMID 17030982), PML reciprocally activates Chk2 by autophosphorylation, and UniProt's residency line is uncoded [E_q95_chek2_loc2]. (2) Centrosomes, MITOSIS ONLY, PLK1-dependent, with the prior constitutive claim shown to be antibody cross-reactivity on a genetic null (PMID 23680298) [E_q95_chek2_loc3]. In interphase, unperturbed cells: nucleoplasm, with no named body.
localization shown for fusion	NO - nobody has looked in any KMT2A fusion, in any lineage, and the bound is 0 records for the gene clause against a subnuclear clause AND the fusion clause from an operand control of 4,921 for the gene clause [E_q95_chek2_loc4]. Stated as a bare NO deliberately (brief rule 86): unlike TRIM27, which has a compartment result in a DIFFERENT fusion, CHK2 has no compartment measurement in any fusion of any kind. This entry also argues that the imaging experiment is the wrong next step - a CHK2 ACTIVITY readout in a KMT2A::AFF1 cell is the measurement the mechanism needs.

kmt2a literature count

{
  "query": "(MLL OR KMT2A) AND CHEK2",
  "count": 2,
  "on_topic_after_title_check": 0,
  "date": "2026-09-20",
  "aliases_run": [
    "CHEK2",
    "CHK2"
  ],
  "aliases_deliberately_not_run": [
    "RAD53 (yeast collision)",
    "CDS1 (CDP-diacylglycerol synthase 1 collision)"
  ]
}

experiments that would separate it

[
  "selective CHK2 inhibitor or CHEK2 knockout substituted for chidamide in the MI-3 combination",
  "ATM inhibitor substituted as the upstream arm - reproduces a CHK2-dependent effect, not a CHK1-dependent one",
  "epistasis of CHEK2 loss with the fusion in a KMT2A::AFF1 line"
]

depmap kmt2a selectivity

{
  "chronos_mean_kmt2a_rearranged": 0.3072,
  "chronos_mean_other_leukaemia": 0.1614,
  "difference": 0.1458,
  "pan_essentiality_all_lines": 0.2195,
  "selectivity_rank": 17416,
  "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."
}

localization

{
  "CONSTITUTIVE": "NUCLEUS in interphase - and there is NO evidence code anywhere in UniProt O96017's subcellular location comment, which carries six values all with empty evidence lists [E_q95_chek2_loc1]. The founding experimental statement is that human wee1's substrate kinase system is partitioned across the envelope: the 1993 paper that made human WEE1 a nuclear protein also established that cdc25C is cytoplasmic, and the nuclear residence of the checkpoint machinery is the point of it.",
  "CONDITIONAL_DAMAGE": "PML NUCLEAR BODIES and the damage-persistent DNA-SCARS. PML-body number rises after double-strand breaks by supramolecular fission, and that rise is delayed or inhibited by loss of NBS1, ATM, Chk2 or ATR; the ATM-hCds1/Chk2-PML axis carries p53-independent irradiation-induced apoptosis [E_q95_chek2_loc2]. UniProt's 'Recruited into PML bodies together with TP53' is uncoded.",
  "CONDITIONAL_MITOSIS": "CENTROSOMES, and ONLY in mitosis - PLK1-dependent, from early mitosis to cytokinesis, nucleus in interphase; and the earlier reports of constitutive centrosomal CHK2 were ANTIBODY CROSS-REACTIVITY with an unknown centrosomal protein [E_q95_chek2_loc3].",
  "ISOFORM_RESOLVED": "uncoded but specific: isoform 12 is annotated to PML body and nucleoplasm, and isoform 10 is 'present throughout the cell' [E_q95_chek2_loc1]. A single resting-state answer for this gene would be wrong three times over - by phase, by damage state and by isoform.",
  "systems": "HCT116 colon carcinoma (wild-type and CHK2-null), U2OS osteosarcoma, and human fibroblast senescence models. Nothing haematopoietic."
}

cell type

{
  "expressed_in": "UniProt tissue specificity, fetched 2026-09-22: 'High expression is found in testis, spleen, colon and PERIPHERAL BLOOD LEUKOCYTES. Low expression is found in other tissues.' That is a haematopoietic expression statement, which is more than most genes in this tranche have - and it is an expression statement, not a localisation or requirement one (concept-expressed-required-maintains-three-evidence-classes).",
  "imaged_in": "HCT116 and U2OS only. No blood cell of any kind has been imaged for CHK2 in the literature this beat could reach [E_q95_chek2_loc3][E_q95_chek2_loc4].",
  "in_kmt2a_r": "NOTHING. 0 records for the gene clause against a subnuclear clause and the fusion clause [E_q95_chek2_loc4]."
}

cell state

{
  "PHASE": "mitosis adds a centrosomal pool; interphase has none [E_q95_chek2_loc3].",
  "DAMAGE": "double-strand breaks reorganise PML bodies in a CHK2-dependent way, and the persistent form (DNA-SCARS) sustains senescence growth arrest and inflammatory cytokine secretion [E_q95_chek2_loc2]. Maps to cell-state-replication-stress-icl-repair.",
  "SENESCENCE": "the DNA-SCARS result makes a compartment a marker of an irreversible state rather than of a cell-cycle position - the structures persist and keep signalling [E_q95_chek2_loc2].",
  "what_is_constitutive_versus_induced": "CONSTITUTIVE: nuclear residence. INDUCED BY DAMAGE: PML-body remodelling and DNA-SCARS. INDUCED BY MITOSIS: the centrosomal subpopulation. Nothing about the compartment is known to depend on differentiation state."
}

localization bounded absence

{
  "date": "2026-09-22",
  "tool": "NCBI E-utilities esearch, db=pubmed",
  "run_by": "Q95",
  "shape": "one [tiab] tag per term (rule 94); cytogenetic terms quoted (rule 95); querytranslation read back and stored (rule 90)",
  "absence_class": "never-measured",
  "queries": {
    "gene_clause_alone": {
      "query": "CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]",
      "count": 4921,
      "querytranslation": "\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]"
    },
    "gene_AND_loc": {
      "query": "(CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab])",
      "count": 548,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract])"
    },
    "gene_AND_subnuclear": {
      "query": "(CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab])",
      "count": 46,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract])"
    },
    "gene_AND_fusion": {
      "query": "(CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 8,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_loc_AND_fusion": {
      "query": "(CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 1,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_subnuclear_AND_fusion": {
      "query": "(CHEK2[tiab] OR CHK2[tiab] OR \"Cds1\"[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 0,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract] OR \"Cds1\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "chk2_pml": {
      "query": "CHEK2[tiab] OR CHK2[tiab]",
      "count": 4649,
      "querytranslation": "\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract]"
    },
    "chk2_pml2": {
      "query": "(CHEK2[tiab] OR CHK2[tiab]) AND (\"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"PML nuclear\"[tiab])",
      "count": 9,
      "querytranslation": "(\"CHEK2\"[Title/Abstract] OR \"CHK2\"[Title/Abstract]) AND (\"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"PML nuclear\"[Title/Abstract])"
    }
  },
  "title_check": "chk2_pml2, 9 records, 9 of 9 genuinely about PML bodies or damage-induced nuclear structures (27468685, 21118958, 20719863, 19556897, 19291793, 17206596, 17030982, 15195100, 12810724) - an uncontaminated compartment query, because 'PML body' is a specific multi-word phrase rather than a single contaminated token.",
  "aliases_searched": [
    "CHEK2",
    "CHK2",
    "Cds1",
    "hCds1 (23 records, measured separately)"
  ]
}

How this could bite us back

Inhibiting CHK2 in this disease means suppressing the effector of a checkpoint that, in the only in vivo test of it, acted as a barrier against MLL-ENL leukaemogenesis. The therapeutic and the leukaemogenic direction are the same intervention at different stages.
CHEK2 is a germline tumour-suppressor gene in the general population. A CHK2-directed agent in a child is pharmacological phenocopy of a cancer-predisposition genotype, for the duration of dosing, in every tissue.
Because no result in this disease separates CHK2 from CHK1, a trial designed around 'checkpoint disruption' cannot say which kinase it is testing, and a negative result would not be attributable.

Still open

Is CHK2 required for the chidamide + menin-inhibitor synergy, or is it a phospho-passenger? One selective-inhibitor arm answers it.
Do germline CHEK2 variants occur at elevated frequency in children with KMT2A-rearranged leukaemia? CHEK2 is on paediatric predisposition panels and no study in this disease reports it either way - an absence of testing, not a negative.
The MLL-ENL senescence barrier runs through CHK2. Is that barrier intact in a human fetal progenitor carrying KMT2A::AFF1? If it is, it is the strongest reason to expect that most fetal KMT2A breaks never become leukaemia - which is what this graph's break-machinery beat independently concludes from base rates.

Every source behind this entry (9)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
CHEK2 is UniProt O96017, serine/threonine-protein kinase Chk2, 543 residues, primary gene name CHEK2 with synonyms CDS1, CHK2 and RAD53; the paralogue CHEK1 is O14757 at 476 residues.
UniProtKB O96017 (CHK2_HUMAN), Serine/threonine-protein kinase Chk2, 543 aa, primary gene name CHEK2, synonyms CDS1 CHK2 RAD53 · UniProt Consortium 2026
What this evidence cannot show
A naming fact. gene_exact:CHEK2 AND organism_id:9606 AND reviewed:true returned exactly one row with gene_primary CHEK2. The synonym RAD53 is a yeast gene name carried as a human synonym and is a live collision risk for any text-mining route.
Evidence that argues against this (1)
- The paralogue control matters more here than usual because the two kinases are almost always written together. O14757 is 476 aa against O96017's 543, so a swap is length-detectable; nothing in the protein names would catch it, since both read 'Serine/threonine-protein kinase Chk'. UniProt Consortium 2026
E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Combined chidamide and MI-3 disrupted the DNA damage checkpoint at the level of CHK1 and CHK2 kinases rather than their upstream kinases ATR and ATM in MLL-rearranged AML cells.
Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair. · Ye J, Zha J, Shi Y, Li Y, Yuan D, Chen Q, et al. · Clin Epigenetics 2019
PMID 31590682 DOI
What this evidence cannot show
CHK2 is named as half of a pair. No CHEK2-specific perturbation was performed, so the study establishes that p-CHK2 changes, not that CHK2 is required for the synergy. Myeloid cell lines, tool menin inhibitor, one group.
Evidence that argues against this (1)
- A phospho-CHK2 decrease is exactly what would be seen if the effect were entirely upstream at ATM, which the same authors say it is not - but the evidence for that exclusion is also a phospho-western, and the second chidamide combination in the same lines reports p-ATM and p-ATR falling as well. The localisation within the cascade is therefore contested by the only two studies that address it. Zhang Q et al. 2024
E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In MLL-rearranged AML lines Molm-13 and MV4-11, chidamide plus (+)-JQ-1 reduced p-CHK2 together with p-CHK1, p-ATR and p-ATM, while the non-MLL-rearranged line Kasumi showed no comparable change.
[Chidamide Combined with (+) -JQ-1 to Kill MLL-Rearrangement Acute Myeloid Leukemia Cells by Disrupting the DNA Damage Response Pathway]. · Zhang Q, Li FM, Wang W, Zhang ZH, Zhang RJ, Ma MS, et al. · Zhongguo Shi Yan Xue Ye Xue Za Zhi 2024
PMID 39479812 DOI
What this evidence cannot show
Abstract only; three cell lines; western blot; no CHEK2-specific perturbation; single non-MLL-r comparator confounded by genotype differences other than the rearrangement.
Evidence that argues against this (1)
- Ye et al. report that the same class of combination acts at CHK1/CHK2 and explicitly NOT at ATR/ATM. Both cannot be right about where in the cascade the effect sits, and neither performed the epistasis experiment that would settle it. Ye J et al. 2019
E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MLL-ENL oncogene activation in mice induces an ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence as a fail-safe barrier at early stages of transformation; inhibiting the barrier accelerated leukaemia development.
DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo. · Takacova S, Slany R, Bartkova J, Stranecky V, Dolezel P, Luzna P, et al. · Cancer Cell 2012
PMID 22516260 DOI
What this evidence cannot show
CHK2 is again named as part of a four-node chain and not perturbed individually. Mouse, MLL-ENL, regulatable system. The value of this citation in a CHEK2 entry is that it shows the kinase on the tumour-SUPPRESSIVE side of the ledger in this oncogene, which is the direction a combination therapy has to argue against.
Evidence that argues against this (1)
- The therapeutic results in established KMT2A-rearranged disease run the other way, with checkpoint disruption as the killing mechanism. Stage - transformation versus established leukaemia - is the plausible reconciliation, and no study in this disease has measured both stages in one system. Ye J et al. 2019
E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
As of 2026-09-20 the PubMed query (MLL OR KMT2A) AND CHEK2 returns 2 records and title-checking finds neither is about KMT2A-rearranged leukaemia: one is a bovine cumulus-cell cuproptosis study and one is a follicular thyroid cancer sequencing paper.
PubMed esearch, db=pubmed, term '(MLL OR KMT2A) AND CHEK2', run 2026-09-20; count 2; both titles read from a full efetch record and judged off-topic · NCBI PubMed 2026
What this evidence cannot show
A counted absence and only as good as its symbol set. The HGNC symbol badly undercounts this literature - the sibling case is decisive, where (MLL OR KMT2A) AND CHEK1 returns 1 record and the same query with CHK1 returns 5. The CHK2 form was therefore also run, and the additional records it surfaces are the two chidamide papers already cited here [E2, E3] plus the MLL-ENL barrier paper [E4], all of which name CHK2 without measuring it separately. Synonyms CDS1 and RAD53 were NOT run as separate queries: RAD53 collides with the yeast literature and CDS1 with CDP-diacylglycerol synthase 1, so both would inflate rather than inform.
Evidence that argues against this (1)
- The absence is about member-level measurement, not about presence in the literature. CHK2 is present in three of the most cited results in this beat - it is simply never the variable. A reader who takes the count of 2 as 'CHK2 is unstudied in this disease' would be wrong in the opposite direction, which is why the caveat enumerates where it does appear. Ye J et al. 2019
E_q95_chek2_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt O96017 carries SIX subcellular location values for CHK2 and EVERY ONE OF THEM HAS AN EMPTY EVIDENCE LIST - there is not a single evidence code of any class in the entire SUBCELLULAR LOCATION comment, experimental or inferred. The uncoded values include 'Nucleus' for the canonical protein, 'Nucleus' repeated for isoforms 2, 4, 7 and 9, 'Nucleus, PML body' and 'Nucleus, nucleoplasm' for isoform 12, the note 'Recruited into PML bodies together with TP53', and the note 'Isoform 10 is present throughout the cell'.
UniProtKB O96017 (CHK2_HUMAN), SUBCELLULAR LOCATION comments for the canonical sequence and for isoforms 2, 4, 7, 9, 10 and 12, with evidence lists read back from the raw JSON, fetched live 2026-09-22 · UniProt Consortium · Databases 2026
What this evidence cannot show
A statement about the database record, not about the biology - CHK2 is unambiguously nuclear and nobody disputes it. What this establishes is that for this protein there is nothing to filter: the graph's usual discipline of separating ECO:0000269 from ECO:0000250 and ECO:0000305 has no purchase, because a filter on any evidence code discards the WHOLE record including its most interesting lines.
Evidence that argues against this (1)
- THIS IS THE KMT2A PATTERN FROM BRIEF RULE 91, WITH THE SIGN REVERSED, AND IT ARGUES FOR READING UNCODED COMMENTS RATHER THAN AGAINST THE DATABASE. Rule 91's worked example is KMT2A, where the full-length protein carries three ECO:0000269s and both taspase1-fragment comments are UNCODED - so an ECO:0000269 filter keeps the least useful line and discards the two fragment-scoped ones. Here there is no coded line to keep, and the uncoded lines are ISOFORM-scoped and carry the two most specific statements in the record: isoform 12 in PML bodies and the nucleoplasm, and isoform 10 present throughout the cell. Both are real, checkable claims about which CHK2 species goes where. An automated quality pass that scored this record on evidence codes would rate it zero and delete the only isoform-resolved compartment map of a cell-cycle kinase in this graph. Heald R et al. 1993
E_q95_chek2_loc2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CHK2's constitutive compartment is the NUCLEUS in interphase and its subnuclear addresses are CONDITIONAL, not constitutive. After DNA double-strand-break induction the number of PML nuclear bodies increases by a supramolecular fission mechanism, and that increase is DELAYED OR INHIBITED by loss of function of NBS1, ATM, Chk2 and ATR - so CHK2 is required for the damage-induced remodelling of the compartment it is annotated to. The pathway is genetic as well as structural: hCds1/Chk2 mediates gamma-irradiation-induced apoptosis p53-independently through an ATM-hCds1/Chk2-PML axis.
Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. · Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG, Bazett-Jones DP · J Cell Biol 2006
PMID 17030982 DOI
What this evidence cannot show
Read precisely, PMID 17030982 makes CHK2 a REGULATOR of PML-body number rather than a resident of the bodies; the residency claim is UniProt's uncoded 'Recruited into PML bodies together with TP53' and the ATM-Chk2-PML pathway paper, which is functional. The distinction matters because a kinase can control a compartment it never enters. The damage-persistent form of these structures - DNA-SCARS, which retain checkpoint proteins and sustain senescence growth arrest and inflammatory cytokine secretion (PMID 21118958) - is the strongest available evidence that checkpoint kinase signalling and PML bodies share a physical location over time.
Evidence that argues against this (1)
- A DIRECT AND SPECIFIC OBJECTION TO THE OTHER DIRECTION OF THE SAME RELATIONSHIP, WHICH WEAKENS THE ARGUMENT THAT PML BODIES SIMPLY HOST CHK2: PML has been reported to ACTIVATE Chk2 by mediating its autophosphorylation, and a separate study finds REGgamma/PA28gamma interacting with both PML and Chk2 and altering PML-body number. So the causal arrow runs both ways and the third factor is a proteasome activator. Taken together the honest reading is a mutual dependency between a kinase and a body rather than a compartment assignment, and this entry should not be quoted as 'CHK2 localises to PML bodies' without the word conditional. What no source has done is image endogenous CHK2 in PML bodies in an unperturbed haematopoietic cell. Zannini L et al. 2009
E_q95_chek2_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CHK2's one strictly PHASE-DEPENDENT compartment is the centrosome and it exists only in mitosis: using wild-type and CHK2-null HCT116 cells and CHK2-depleted U2OS cells with inducible GFP-CHK2 and Flag-CHK2 fusions, CHK2 localises to the nucleus in interphase while a fraction associates with centrosomes in a Polo-like-kinase-1-dependent manner from early mitosis until cytokinesis - and the same paper shows that several commercial CHK2 antibodies are NON-SPECIFIC and cross-react by immunofluorescence with an unknown centrosomal protein, which is what produced the earlier literature reporting centrosomal CHK2 throughout the cell cycle.
Cell cycle-dependent localization of CHK2 at centrosomes during mitosis. · Chouinard G, Clément I, Lafontaine J, Rodier F, Schmitt E · Cell Div 2013
PMID 23680298 DOI
What this evidence cannot show
Human colon carcinoma and osteosarcoma lines, with tagged constructs for the positive result because the antibodies could not be trusted - so the localisation rests on overexpressed fusions validated against genetic nulls rather than on endogenous staining. It is a minority pool by the authors' own words ('a subpopulation'), and nothing in this paper is haematopoietic.
Evidence that argues against this (1)
- THIS IS A BRIEF-RULE-74 EVENT AND IT SHOULD CHANGE HOW THIS GRAPH READS ITS OWN CENTROSOMAL CLAIMS, INCLUDING ONES IT LIKES. The published constitutive-centrosomal-CHK2 result was an antibody artefact, demonstrated by putting the same antibodies on a genetic null. This graph currently carries two centrosomal assignments in adjacent tranches - WDR5 at the centrosome and midbody, and tranche 5's finding that KAT2A and KAT2B sit at centrosomes in late G1 and acetylate PLK4 - and neither was checked against a null cell for antibody specificity. The centrosome is a small, protein-dense, autofluorescence-prone structure that attracts false positives, and a cross-reacting band there is invisible to every control short of a knockout. The argument is not that those results are wrong; it is that a centrosomal immunofluorescence claim in this corpus has a documented failure mode and should carry the genetic-null control in its caveat. Rodier F et al. 2011
E_q95_chek2_loc4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
Bounded 2026-09-22: no CHK2 compartment has been measured in any KMT2A-fusion cell. The gene clause over CHEK2, CHK2 and 'Cds1' returns 4,921 records and intersects the nine-term KMT2A/MLL fusion clause at 8; with a localisation clause the gene clause returns 548 and with the fusion clause added 1; with a subnuclear clause it returns 46 and with the fusion clause added 0. The PML sub-query returns 9 records, all of which are PML-body or DNA-damage-structure papers and none of which is in a KMT2A-rearranged cell.
NCBI E-utilities esearch db=pubmed; every count stored with the querytranslation read back, in data.localization_bounded_absence · NCBI E-utilities · Databases 2026
What this evidence cannot show
Titles and abstracts only; supporting figures not searched (brief rule 80), and for a checkpoint kinase that is a real limitation because an immunofluorescence panel showing nuclear CHK2 in a leukaemia line would be a supporting figure in a paper about something else. The absence is about a MEASURED COMPARTMENT: this entry's own body already records that CHEK2 is named in every combination mechanism here and measured on its own in none of them, and the localisation gap is the same gap.
Evidence that argues against this (1)
- THE ABSENCE IS SOFTER THAN THE COUNT SUGGESTS BECAUSE THE COMPARTMENT QUESTION FOR THIS PROTEIN IS ALMOST CERTAINLY NOT THE INTERESTING ONE. CHK2 is nuclear everywhere anyone has looked, and its two conditional addresses are triggered by damage and by mitosis - neither of which is a property of the fusion. The quantity a KMT2A::AFF1 argument would actually need is not where CHK2 is but whether the fusion's replication-stress phenotype is already engaging it, which is an activity measurement (phospho-T68, KAP1-S824 or a CHK2 substrate panel) and not a localisation one. Recording a bounded localisation absence here is therefore correct bookkeeping and a weak research lead, and this entry says so rather than implying an imaging experiment is the missing step. Chouinard G et al. 2013

Connected to

← related toCHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
paralogue pair, different branches: CHK1 the ATR effector, CHK2 the ATM effector
depends on →ATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners
CHK2 is the ATM effector; named in every combination mechanism here and measured separately in none
related to →CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
paralogue pair on different branches, written as one compound noun in three key results
← inhibitsChidamide (tucidinostat) - the HDAC inhibitor in both of this graph's menin-inhibitor combination papers, and the only one paired with a menin inhibitor in the lymphoid index disease
p-CHK2 falls with p-CHK1 in both published chidamide combinations
related to →KMT2A-rearranged acute myeloid leukaemia in children and infants
counted absence: (MLL OR KMT2A) AND CHEK2 returns 2 records, neither on topic
related to →PML nuclear bodies and PML::RARA — the best-worked case of a fusion destroying a nuclear compartment, and what it actually predicts for KMT2A
CHK2's damage-conditional subnuclear address. PML-body number rises after double-strand breaks by supramolecular fission and the rise is delayed or inhibited by loss of NBS1, ATM, Chk2 or ATR (PMID 17030982); the ATM-hCds1/Chk2-PML axis carries p53-independent irradiation apoptosis (PMID 12402044). Note CHK2 is as much a REGULATOR of body number as a resident, and UniProt's residency line is uncoded (Q95 2026-09-22)
related to →WDR5 and KMT2A are at the centrosome and the midbody - a non-chromatin address for both, with a patient-cell phenotype
A RULE-74 WARNING FOR THIS GRAPH'S CENTROSOMAL CLAIMS. CHK2 localises to centrosomes ONLY in mitosis, PLK1-dependently, and the earlier constitutive-centrosomal literature was shown to be ANTIBODY CROSS-REACTIVITY with an unknown centrosomal protein, demonstrated on CHK2-null HCT116 cells (PMID 23680298). Neither this node's WDR5 claim nor tranche 5's KAT2A/PLK4 centrosome finding carries a genetic-null antibody control (Q95 2026-09-22)
related to →Replication stress and interstrand-crosslink repair as a cell state - an ATR dependency measured in mouse MLL-rearranged AML, and the same stress implicated in breaking the MLL locus in the first place
CHK2's compartment is state-defined rather than position-defined: damage produces PML-body remodelling and the persistent DNA-SCARS structures that sustain senescence growth arrest and inflammatory cytokine secretion (PMID 21118958). Constitutive = nuclear; damage-induced = PML/DNA-SCARS; mitosis-induced = centrosomal (Q95 2026-09-22)