Oncofusion

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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q43-break-repair-machinery

WEE1 - the one checkpoint target with a KMT2A::AFF1-specific result, and the paper that also found the escape route

also called WEE1 · WEE1hu · Wee1A kinase · Wee1-like protein kinase

WEE1 holds a cell at the gate before it divides. Blocking it forces damaged leukaemia cells through that gate to their death, and among all types of childhood ALL the cells that recover least from this are the KMT2A-rearranged ones. The same study found the survivors change identity to escape, and what to give next.

The same thing, for a scientist

WEE1 (P30291, 646 aa) is the tyrosine kinase that enforces the G2/M checkpoint by inhibitory phosphorylation of CDK1. Malyukova et al. characterised G2/M checkpoint inhibition across acute lymphoblastic leukaemia and found **the highest inhibition of recovery of proliferation in ALL cells with KMT2A rearrangements** [E2]. Single-cell RNA-seq and ATAC-seq of RS4;11 - the KMT2A::AFF1 line, the index fusion of this graph - under the WEE1 inhibitor AZD1775 showed diversification of cell states with a fraction of cells activating p53-driven apoptosis and senescence programmes, and **disruption of a core KMT2A-RUNX1-MYC regulatory network** [E2]. That last clause is what lifts this above a generic cell-cycle result: the effect is reported as reaching the fusion's own transcriptional circuit and not only the cell cycle. The same paper contains its own counter-argument. A subpopulation transitions **reversibly** to a drug-tolerant state defined by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling, and the authors' answer is sequential administration of dasatinib, ibrutinib, fatostatin or AZD2014 [E2]. So the honest summary is: best-supported checkpoint target in the index fusion, with a documented non-genetic resistance mechanism and a proposed sequencing strategy, all from one study.

Go deeper
Why this is the strongest checkpoint result in the beat

Three properties, none of which the ATR, CHK1 or CHK2 results have together:

  1. The index fusion, not a surrogate. RS4;11 carries KMT2A::AFF1. The ATR results use MLL-ENL plus N-RAS (myeloid) or Mll-Af4 plus N-Ras^G12D (lymphoid but RAS-dependent).
  2. A comparative claim across ALL subtypes, with KMT2A-rearranged at the top for failure to recover proliferation - a selectivity statement rather than a single-arm sensitivity.
  3. A mechanistic link to the fusion's own programme via disruption of a KMT2A-RUNX1-MYC network, measured by single-cell RNA-seq and ATAC-seq.

What it does not have: an in vivo arm reported in the abstract, a primary infant sample, or independent replication.

The escape the authors found themselves

The drug-tolerant state is non-genetic and reversible, characterised by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling. That is a different class of resistance from a MEN1 binding-site mutation and it has a different implication: it predicts that a WEE1 inhibitor used as a single agent will select a persistent population rather than being defeated by a mutation, and that the persistence is addressable by changing the second agent rather than the first.

The proposed second agents - dasatinib, ibrutinib (pre-BCR signalling), fatostatin (SREBP/lipid), AZD2014 (mTOR) - are all agents with existing clinical experience, which makes the sequencing proposal unusually actionable for a graph that mostly holds tool compounds.

Facts and figures
uniprotP30291
length AA646
gene symbolWEE1
accession resolutiongene_exact:WEE1 AND organism_id:9606 AND reviewed:true returned exactly 1 row; gene_primary WEE1, length 646.
checkpointG2/M, via inhibitory phosphorylation of CDK1
tool compoundAZD1775 (adavosertib)
in vivo arm reported in abstractfalse
independent replicationnone found
subnuclear localizationNONE ASSIGNED - A BOUNDED ABSENCE, and the tranche's starkest mismatch between clinical attention and compartment knowledge. A twelve-term subnuclear clause returns 12 records and not one is a WEE1 compartment measurement (they are nucleolar-integrity, Def-CAPN3 and Capn3-depletion studies in which Wee1 is a substrate or an accumulating protein); there is no reported nuclear export, no mapped NLS, no named body, and no compartment measurement of any kind since 1993 [E_q95_wee1_loc2]. This matters more here than for most genes because the founding paper's argument is that the compartment is the mechanism, and WEE1 is an active clinical target (adavosertib/AZD1775) with one KMT2A::AFF1-specific result already in this entry.
localization shown for fusionNO - nobody has looked in any KMT2A fusion, in any lineage, and the bound is 0 for the gene clause against a localisation clause AND the fusion clause and 0 against a subnuclear clause AND the fusion clause, from 5 records placing WEE1 and a fusion term in one abstract [E_q95_wee1_loc2]. What makes this NO unusual in this tranche: the index-fusion experiment EXISTS - AZD1775 in RS4;11 with single-cell RNA-seq and ATAC-seq [E_q95_wee1_loc3] - so the cells, the drug and the timepoints are all in hand and only the compartment readout was never taken.
index fusion evidence
{
  "cell_line": "RS4;11",
  "fusion": "KMT2A::AFF1",
  "assays": [
    "single-cell RNA-seq",
    "single-cell ATAC-seq"
  ],
  "comparative_claim": "highest inhibition of recovery of proliferation among ALL subtypes tested",
  "network_effect": "disruption of a core KMT2A-RUNX1-MYC regulatory network",
  "pmid": "38822412",
  "title": "Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.",
  "authors": "Malyukova A, Lahnalampi M, Falqués-Costa T, et al.",
  "venue": "Genome Biol",
  "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."
}
resistance
[
  "reversible non-genetic transition to a drug-tolerant state defined by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling",
  "counteracted in the same study by sequential dasatinib, ibrutinib, fatostatin or AZD2014"
]
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -2.578,
  "chronos_mean_other_leukaemia": -2.6316,
  "difference": 0.0536,
  "pan_essentiality_all_lines": -2.5831,
  "selectivity_rank": 15016,
  "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, on ONE ECO:0000269 from 1993 - and for once the citation is exactly on point, because the compartment IS the mechanism: human wee1 is a nuclear kinase and its substrate's activator cdc25C is cytoplasmic and enters the nucleus only at G2/M, so nuclear wee1 protects the nucleus from cytoplasmically activated cdc2 [E_q95_wee1_loc1].",
  "WHAT_IS_CONSTITUTIVE_VERSUS_PHASE_DEPENDENT": "WEE1's OWN compartment is not reported to change with phase - what changes is the partitioning of the players around it: cdc25C and cyclin B1 enter the nucleus at the G2/M transition [E_q95_wee1_loc1]. So unlike CHEK2 and CDK4 in this same tranche, WEE1's phase dependence is in the SYSTEM rather than in the protein, and no phase-resolved WEE1 localisation experiment exists to say otherwise [E_q95_wee1_loc2].",
  "no_determinant_mapped": "no NLS is annotated in UniProt P30291's feature table and none has been published; an NLS-and-transport literature probe returns 32 records with no paper about WEE1's own determinants [E_q95_wee1_loc2].",
  "systems": "unspecified human cells in the 1993 paper; the KMT2A::AFF1 line RS4;11 for the functional work, where no compartment was measured."
}
cell type
{
  "measured_in_this_disease": "RS4;11, a human KMT2A::AFF1 B-lineage line - functionally, by single-cell RNA-seq and single-cell ATAC-seq, with no compartment readout [E_q95_wee1_loc3]. This is a B-lineage, human, index-fusion system, which is rare in this corpus.",
  "imaged_in": "unspecified cells, once, in 1993 [E_q95_wee1_loc1]. No haematopoietic cell has ever been imaged for WEE1 in the reachable literature.",
  "expression": "UniProt P30291 carries no tissue-specificity comment."
}
cell state
{
  "G2_M_CHECKPOINT": "the state WEE1 exists to enforce, via inhibitory phosphorylation of CDK1 [E_q95_wee1_loc1].",
  "DRUG_TOLERANT_PERSISTER": "the escape state is reversible and NON-GENETIC, defined by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling, and counteracted in the same study by sequential dasatinib, ibrutinib, fatostatin or AZD2014 [E_q95_wee1_loc3]. Maps to cell-state-relapse-initiating-persister.",
  "no_compartment_in_either_state": "neither the AZD1775-sensitive nor the drug-tolerant state has a WEE1 localisation measurement, so the checkpoint setpoint cannot currently be related to nuclear WEE1 concentration [E_q95_wee1_loc2]."
}
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": "WEE1[tiab] OR \"Wee1A\"[tiab]",
      "count": 2053,
      "querytranslation": "\"WEE1\"[Title/Abstract] OR \"Wee1A\"[Title/Abstract]"
    },
    "gene_AND_loc": {
      "query": "(WEE1[tiab] OR \"Wee1A\"[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab])",
      "count": 238,
      "querytranslation": "(\"WEE1\"[Title/Abstract] OR \"Wee1A\"[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": "(WEE1[tiab] OR \"Wee1A\"[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": 12,
      "querytranslation": "(\"WEE1\"[Title/Abstract] OR \"Wee1A\"[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": "(WEE1[tiab] OR \"Wee1A\"[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": 5,
      "querytranslation": "(\"WEE1\"[Title/Abstract] OR \"Wee1A\"[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": "(WEE1[tiab] OR \"Wee1A\"[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": 0,
      "querytranslation": "(\"WEE1\"[Title/Abstract] OR \"Wee1A\"[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": "(WEE1[tiab] OR \"Wee1A\"[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": "(\"WEE1\"[Title/Abstract] OR \"Wee1A\"[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])"
    },
    "wee1_centrosome": {
      "query": "WEE1[tiab] AND (centrosome*[tiab] OR spindle[tiab] OR mitotic[tiab])",
      "count": 534,
      "querytranslation": "\"WEE1\"[Title/Abstract] AND (\"centrosome*\"[Title/Abstract] OR \"spindle\"[Title/Abstract] OR \"mitotic\"[Title/Abstract])"
    },
    "wee1_nuclear": {
      "query": "WEE1[tiab] AND (nuclear[tiab] OR nucleus[tiab])",
      "count": 187,
      "querytranslation": "\"WEE1\"[Title/Abstract] AND (\"nuclear\"[Title/Abstract] OR \"nucleus\"[Title/Abstract])"
    }
  },
  "extra_probe": {
    "query": "WEE1[tiab] AND (\"nuclear export\"[tiab] OR \"nuclear localization\"[tiab] OR \"subcellular localization\"[tiab] OR NLS[tiab])",
    "count": 32,
    "querytranslation": "\"WEE1\"[Title/Abstract] AND (\"nuclear export\"[Title/Abstract] OR \"nuclear localization\"[Title/Abstract] OR \"subcellular localization\"[Title/Abstract] OR \"NLS\"[Title/Abstract])",
    "title_check": "first 12 read; 0 about WEE1's own localisation determinants"
  },
  "title_check": "gene_AND_subnuclear, 12 records, 0 a WEE1 compartment measurement - 34452850 and 32588143 (Def-CAPN3 nucleolar degradation pathway and Capn3 depletion causing Wee1 accumulation), 29881774 (nucleolar integrity supporting Cdk1 activation), 24006256 (fission yeast nucleolar Dnt1 downregulating Wee1) and eight others where Wee1 is a network node.",
  "aliases": "UniProt lists NO gene synonyms for WEE1. WEE2/Wee1B is a DIFFERENT gene with an oocyte phenotype and was deliberately excluded rather than searched as an alias."
}
How this could bite us back
  • WEE1 inhibition works by forcing cells with damaged DNA through mitosis. In a surviving normal progenitor that is mitotic catastrophe for most cells and a missed checkpoint for a few, and the few are the ones that matter for a second malignancy in a child with decades of life ahead.
  • The same G2/M checkpoint is an arm of the DDR barrier that limited MLL-ENL leukaemogenesis in vivo; releasing it is directionally the intervention that accelerated transformation in that model.
  • The resistance mechanism is non-genetic, reversible and already documented by the discovering study. A single-agent trial would therefore be expected to produce responses followed by regrowth from a persister pool, and would be read as failure unless the sequencing strategy is built in from the start.
  • AZD1775's selectivity is imperfect and the KMT2A-specific claim is made pharmacologically. Before this is built on, a genetic WEE1 perturbation in a KMT2A::AFF1 line should reproduce the comparative advantage.
  • Combining a checkpoint-releasing agent with the cytotoxic backbone these infants already receive stacks genotoxicity on genotoxicity; the TINI experience in this graph shows that infection rather than leukaemia killed four of fifty infants on a regimen with one added epigenetic agent.
Still open
  1. Does WEE1 inhibition work in primary infant KMT2A::AFF1 blasts and in a PDX? The strongest result in this part of the beat has no in vivo arm reported in its abstract.
  2. Is the KMT2A-RUNX1-MYC network disruption a cause of the killing or a consequence of the cell-state diversification? The single-cell design shows both happening and cannot order them.
  3. Does the drug-tolerant pre-BCR state overlap with the lineage-switch phenotype that defeats blinatumomab and CAR-T in this disease? If a WEE1 inhibitor drives cells toward a pre-B programme, its interaction with immunotherapy sequencing is not obviously benign and nobody has looked.
  4. Would a WEE1 inhibitor combine with or antagonise a menin inhibitor? Both are reported to act on the fusion's transcriptional programme, and no combination data exist.
Every source behind this entry (6)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    WEE1 is UniProt P30291, Wee1-like protein kinase, 646 residues, primary gene name WEE1 with no listed synonyms in the reviewed human record.

    What this evidence cannot show

    A naming fact. gene_exact:WEE1 AND organism_id:9606 AND reviewed:true returned exactly one row with gene_primary WEE1. The human paralogue PKMYT1 (WEE2/MYT1 family) was NOT resolved here and is a distinct gene; nothing in this entry should be read as covering it.

    Evidence that argues against this (1)
    • The compound almost always used to make WEE1 claims, AZD1775 (adavosertib), has documented off-target activity against PLK1 and other kinases at concentrations used in cell culture. A WEE1 attribution made from AZD1775 alone is therefore subject to the same naming-versus-measurement caution this graph applies to family-selective inhibitors, and the cited study's genetic controls are not described in its abstract. UniProt Consortium 2026
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In a characterisation of G2/M checkpoint inhibition across acute lymphoblastic leukaemia, the highest inhibition of recovery of proliferation was found in ALL cells with KMT2A rearrangements; single-cell RNA-seq and ATAC-seq of RS4;11 cells harbouring KMT2A::AFF1 treated with the WEE1 inhibitor AZD1775 revealed diversification of cell states, with a fraction of cells showing strong activation of p53-driven apoptosis and senescence processes and disruption of a core KMT2A-RUNX1-MYC regulatory network, while a subpopulation transitioned reversibly to a drug-tolerant state characterised by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling; sequential treatment with dasatinib, ibrutinib, fatostatin or AZD2014 counteracted the drug tolerance.

    Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia. · Malyukova A, Lahnalampi M, Falqués-Costa T, Pölönen P, Sipola M, Mehtonen J, et al. · Genome Biol 2024
    PMID 38822412DOI
    What this evidence cannot show

    Cell lines and single-cell genomics; the abstract does not report an in vivo arm or primary infant material. The mechanistic reading rests on AZD1775 pharmacology rather than on a WEE1 degron. 'Highest inhibition of recovery of proliferation' is a comparative ranking across subtypes in the panel tested, and the composition of that panel determines what 'highest' means. The full text was not read in this beat; all claims here are from the abstract.

    Evidence that argues against this (1)
    • The G2/M checkpoint this drug releases is part of the same DNA-damage-response apparatus that, in vivo, acts as a fail-safe senescence barrier limiting MLL-ENL leukaemogenesis - and inhibiting that barrier accelerated leukaemia development. A checkpoint-releasing agent that kills established KMT2A-rearranged blasts by forcing damaged cells through mitosis is, in surviving normal progenitors, doing the thing that accelerated transformation in that model. Takacova S et al. 2012
  3. E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    A separate AML study reaching WEE1 through a different route reports a CDH1-TK1-dependent DNA synthesis pathway as a chemoresistance mechanism.

    PMID 42570285
    What this evidence cannot show

    Recorded as a bounded rejection, not as support. It appears in the (MLL OR KMT2A) AND WEE1 result set, its index biology is nucleotide salvage in AML chemoresistance rather than KMT2A rearrangement, and neither its full text nor its abstract was read in this beat. Anyone re-running this beat should decide independently whether it belongs; the reason it was set aside is that nothing in its title indicates a KMT2A-specific claim.

    Evidence that argues against this (1)
    • The reason to keep it on the record rather than drop it silently is that this project has measured the cost of unrecorded rejections: 65 laboratories publish in this field with nothing cited anywhere in the graph and no way to tell considered from unexamined. Three lines of reason are cheaper than a repeated search. Malyukova A et al. 2024
  4. E_q95_wee1_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    WEE1's compartment rests on ONE paper from 1993 and that paper is exactly the right one - the compartment IS its mechanism. UniProt P30291 carries a single subcellular location value, 'Nucleus', on a single ECO:0000269, PubMed 8348613, which shows that the human wee1-like tyrosine kinase is a NUCLEAR protein that ensures completion of DNA replication before mitosis, and that the cdc2 activator cdc25C is a CYTOPLASMIC protein which, like cyclin B1, enters the nucleus at the G2/M transition - so cdc2 is likely activated in the cytoplasm and requires nuclear localisation to initiate mitotic transformations, and human wee1 coordinates the replication-to-mitosis transition by PROTECTING THE NUCLEUS from that cytoplasmically activated kinase.

    PMID 8348613DOI
    What this evidence cannot show

    A 1993 study, and the abstract does not state the imaging method or the cell type behind the nuclear assignment; the mechanistic argument is inferred from the partitioning of wee1, cdc25C and cyclin B1 rather than from a direct measurement of protected versus unprotected nuclei. No modern replication of the compartment call exists.

    Evidence that argues against this (1)
    • THE APPROPRIATENESS OF THE CITATION IS THE FINDING, AND IT PUTS THIS RECORD IN A MINORITY OF THREE IN THIS TRANCHE. Of the sixteen genes audited here, only BRD3, ARID1A and WEE1 have UniProt compartment citations that are genuinely about the compartment; the other thirteen range from curator inference with no source (SUPT6H), through family rules (ATXN7L3) and circular cross-species loops (WAC), to a nuclear call whose only experimental source argues for cytosolic retention (USP8) and a nuclear-matrix paper filed under an endosome (TRIM27). So rule 91's failure rate in this tranche is 13 of 16 by database-record quality - but it is not uniform, and a beat that assumed the database is unreliable would have discarded three good records including this one. The audit has to be run per gene in both directions, which is what the rule says. Chouinard G et al. 2013
  5. E_q95_wee1_loc2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    Bounded 2026-09-22 and this is the tranche's starkest mismatch between clinical attention and compartment knowledge: WEE1 has NO mapped nuclear localization signal, NO reported nuclear export, NO subnuclear body and no compartment measurement after 1993. The gene clause over WEE1 and 'Wee1A' returns 2,053 records; an NLS-and-transport probe ('nuclear export', 'nuclear localization', 'subcellular localization', NLS) returns 32 and the title-checked first twelve contain not one paper about WEE1's own localisation determinants; the twelve-term subnuclear clause returns 12 and none is a WEE1 compartment - they are nucleolar-integrity, Def-CAPN3 and Capn3-depletion papers in which Wee1 is a downstream substrate or an accumulating protein; and against the nine-term KMT2A/MLL fusion clause the gene clause returns 5, dropping to 0 with a localisation clause and 0 with a subnuclear clause.

    What this evidence cannot show

    Titles and abstracts only; supporting figures not searched (rule 80). The centrosome-and-mitosis probe returns 534 records, which is large - but it is mitotic-regulation biology in which WEE1 is a kinase in a network, not a localisation literature, and none of the title-checked entries assigns WEE1 to the centrosome. 'Wee1A' as an alias adds nothing; WEE1 has no listed UniProt gene synonyms, and WEE2/Wee1B is a different gene with an oocyte phenotype and was deliberately excluded.

    Evidence that argues against this (1)
    • AND THE ABSENCE IS MORE SERIOUS THAN IT WOULD BE FOR ALMOST ANY OTHER GENE IN THIS TRANCHE, BECAUSE ITS OWN FOUNDING PAPER SAYS THE COMPARTMENT IS THE MECHANISM. WEE1 is an active clinical target - adavosertib/AZD1775 - and this entry already records the one KMT2A::AFF1-specific result in the checkpoint space. If nuclear WEE1 works by holding CDK1 inactive in a compartment its activator must enter, then anything that changes WEE1's nuclear concentration changes the checkpoint's setpoint, and the drug's effect should depend on that concentration. Nobody has measured WEE1's compartment in a leukaemic cell, in any phase, with or without the inhibitor, in 33 years. The counterargument is that the inhibitor acts on catalytic activity wherever the enzyme is, so a compartment measurement might change nothing therapeutically - but that argument is untested and the 1993 paper is a reason to doubt it. Malyukova A et al. 2024
  6. E_q95_wee1_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    WEE1's cell type and cell state in this disease are measured and the state is the informative part: in the KMT2A::AFF1 cell line RS4;11, G2/M checkpoint inhibition with AZD1775 produced the HIGHEST inhibition of recovery of proliferation among the acute lymphoblastic leukaemia subtypes tested, with disruption of a core KMT2A-RUNX1-MYC regulatory network read out by single-cell RNA-seq and single-cell ATAC-seq - and the same study defines the escape state, a reversible NON-GENETIC transition to a drug-tolerant state characterised by pre-B-cell-fate transcription factors, lipid metabolism and pre-BCR signalling.

    Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia. · Malyukova A, Lahnalampi M, Falqués-Costa T, Pölönen P, Sipola M, Mehtonen J, Teppo S, Akopyan K, Viiliainen J, Lohi O, Hagström-Andersson AK, Heinäniemi M, Sangfelt O · Genome Biol 2024
    PMID 38822412DOI
    What this evidence cannot show

    A human KMT2A::AFF1 B-lineage cell line, which is unusually well matched for this corpus, but a single cell line with no in vivo arm reported in the abstract and no independent replication found - both already recorded on this entry. No compartment was measured in either the sensitive or the tolerant state, and the single-cell assays read transcription and accessibility, not protein position.

    Evidence that argues against this (1)
    • THE DRUG-TOLERANT STATE IS DEFINED PARTLY BY LIPID METABOLISM, WHICH CONNECTS THIS ENTRY TO ANOTHER GENE IN THIS SAME TRANCHE AND SUPPLIES AN OBJECTION TO READING WEE1 AS A CLEAN TARGET. The persister state's counter-measures in that study include FATOSTATIN, an SREBP inhibitor - and SREBF1 is amended in this tranche with the finding that SREBP-1 protein level in a leukaemic blast is under at least two controls, sterol status and FLT3/AKT/GSK3-driven precursor degradation, neither of them related to WEE1. So the escape route from a WEE1 inhibitor runs through a lipogenic programme whose master regulator is itself a two-state protein nobody has form-resolved in this disease. That makes the sequential-therapy logic in that paper contingent on a measurement (precursor versus nuclear SREBP-1 in a KMT2A-rearranged cell) that has never been made. Malyukova A et al. 2024
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