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Geneweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q43-break-repair-machinery

SMC1A - a bounded absence written with its query: eleven records, none about this disease, and the whole literature is Cornelia de Lange syndrome

also called SMC1A · SMC1 · SMC1L1 · SB1.8 · DXS423E · structural maintenance of chromosomes protein 1A

SMC1A is the other long arm of the cohesin ring and an ATM target in the damage response. Searching for it alongside KMT2A returns eleven papers and not one of them is about this leukaemia - almost all are about a developmental syndrome caused by cohesin mutations. This entry records that absence precisely, with the queries, rather than filling the space with plausible sentences.

The same thing, for a scientist

SMC1A (Q14683, 1233 aa) is the sister ATPase arm to SMC3 in the cohesin ring and, separately, a classical ATM substrate in the S-phase checkpoint. **There is no KMT2A-rearranged evidence for either role**, and this entry exists to state that with its search, because a padded roster entry would be worse than the absence. **The counted absence.** `(MLL OR KMT2A) AND SMC1A` returns 11 records; title-checking finds **0** about KMT2A-rearranged leukaemia [E2]. Seven of the eleven are Cornelia de Lange syndrome or related developmental-genetics papers, where SMC1A is a cohesinopathy gene and 'MLL' appears because KMT2A/KMT2D variants sit on the same diagnostic panels. The remaining hits are a lineage-switch case report, a paediatric AML miR-196b prognosis paper, a short-stature panel study, and a Korean microcephaly genomic analysis. **Rule 64 was applied and it changed the answer, though not for this subunit.** Running the complex form - `(MLL OR KMT2A) AND cohesin`, 17 records - surfaces a preprint titled *'Cohesin loss and MLL-AF9 are not synthetic lethal in murine hematopoietic stem and progenitor cells'* that is unreachable from any subunit symbol [E3]. So the complex has KMT2A-specific literature and SMC1A does not, and the honest statement is at the complex level. **The one thing that is known about SMC1A here comes from the patient break map by proxy:** SMC1A is a cohesin subunit and 517 RAD21 and 256 SMC3 binding sites were preferentially break-prone in KMT2A-rearranged patients [E4]. The study did not use an SMC1A track.

Go deeper
The absence, written so it can be re-run
querycounton-beat after title check
(MLL OR KMT2A) AND SMC1A110
(MLL OR KMT2A) AND cohesin174
(MLL OR KMT2A) AND RAD218(see gene-rad21)
(MLL OR KMT2A) AND SMC38(see gene-smc3)

Aliases considered: SMC1, SMC1L1, SB1.8, DXS423E. SMC1 was not run as a bare query because it is a prefix of SMC1A/SMC1B and of the SMC family generally and would inflate rather than inform - the same reason this project banned SEPT* as a wildcard. DXS423E is a mapped-locus designation from positional cloning and returns nothing useful.

What would change this: any study perturbing SMC1A in a KMT2A-rearranged system, any SMC1A ChIP track intersected with the KMT2A BCR, or any report of SMC1A mutation co-occurring with a KMT2A rearrangement at above-chance frequency.

The ATM connection this entry deliberately does not build on

SMC1A is phosphorylated by ATM at S957 and S966 as part of the S-phase checkpoint, and this graph holds gene-atm, mechanism-atm-atr-men1-stabilisation-dna-damage and a RAD51-loading result in which ATM deficiency causes excessive recombination-protein loading at the 11q23 KMT2A hotspot [see gene-rad51]. Joining those into 'ATM phosphorylates SMC1A at the KMT2A breakpoint' would be a sentence with two true halves and no evidence in the middle, and this project has a documented history of such sentences entering as facts. No study places SMC1A, phosphorylated or otherwise, at the KMT2A locus. It is written here as an open question and nowhere else.

Facts and figures
uniprotQ14683
length AA1233
gene symbolSMC1A
accession resolutiongene_exact:SMC1A AND organism_id:9606 AND reviewed:true returned exactly 1 row; gene_primary SMC1A, length 1233, synonyms DXS423E KIAA0178 SB1.8 SMC1 SMC1L1.
sister subunitgene-smc3 (Q9UQE7, 1217 aa - 16 residues apart; length is a weak discriminator for this pair)
entry typeBOUNDED ABSENCE. No KMT2A-rearranged evidence exists for SMC1A. The entry records the queries rather than padding a roster.
known biology not evidenced hereSMC1A is an ATM substrate (S957/S966) in the S-phase checkpoint; no study places it at the KMT2A locus and this entry makes no such claim
counted absence
{
  "query": "(MLL OR KMT2A) AND SMC1A",
  "count": 11,
  "on_beat_after_title_check": 0,
  "dominant_topic_of_hits": "Cornelia de Lange syndrome and related developmental genetics (7 of 11)",
  "date": "2026-09-20",
  "aliases_considered": [
    "SMC1",
    "SMC1L1",
    "SB1.8",
    "DXS423E"
  ],
  "aliases_deliberately_not_run": [
    "SMC1 bare - prefix collision with SMC1A/SMC1B and the SMC family"
  ],
  "complex_form_run": "(MLL OR KMT2A) AND cohesin, 17 records, 4 on beat - and it surfaced PMID 38352423, unreachable from any subunit symbol",
  "repo_grep": "SMC1A appears in four existing entries. Two name it only inside 'cohesin' (mechanism-loop-anchor-dsb-hotspots, genome-cohesin-architectural-colesion). Two cite PMID 42591212, where SMC1A and TP53 mutations newly emerged at a B-ALL-to-AML lineage switch - and that paper is explicitly about a case WITHOUT KMT2A rearrangement, which is why it does not overturn the absence."
}
what would change this
[
  "any perturbation of SMC1A in a KMT2A-rearranged system",
  "an SMC1A ChIP track intersected with the KMT2A BCR",
  "above-chance co-occurrence of SMC1A mutation with KMT2A rearrangement"
]
closest smc1a datum in this graph
{
  "pmid": "42591212",
  "finding": "TP53 and SMC1A mutations newly emerged at a B-ALL-to-AML lineage switch after inotuzumab ozogamicin, read by the authors as selective expansion of a genetically distinct subclone",
  "why_it_does_not_count": "the case is explicitly non-KMT2A-rearranged; the paper's stated motivation is lineage switch in cases WITHOUT KMT2A rearrangement",
  "already_cited_in": [
    "cell-state-pro-b-arrest",
    "risk-lineage-switch-cd19-directed-therapy"
  ],
  "title": "Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.",
  "authors": "Kondo K, Sadato D, Najima Y, et al.",
  "venue": "Front Immunol",
  "year": 2026,
  "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."
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -1.6676,
  "chronos_mean_other_leukaemia": -1.4788,
  "difference": -0.1888,
  "pan_essentiality_all_lines": -1.2683,
  "selectivity_rank": 289,
  "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."
}
How this could bite us back
  • This entry proposes nothing and its main risk is being read as more than it is. SMC1A is here because the beat enumerated cohesin subunits, not because evidence was found; anyone building on it should start from the absence rather than from the protein's general biology.
  • SMC1A is X-linked and its loss-of-function causes a developmental cohesinopathy. Any intervention directed at it would carry that phenotype as a floor, which alone rules it out in a paediatric population.
Still open
  1. Is SMC1A, or ATM-phosphorylated SMC1A, present at the KMT2A breakpoint cluster region? ATM is known to limit RAD51 loading at that hotspot and SMC1A is a canonical ATM substrate, but joining those two facts is an inference nobody has tested and this entry deliberately does not make.
  2. Does any published cohesin ChIP dataset in a haematopoietic progenitor include an SMC1A track overlapping chr11:118.48 Mb? This is a public-data question with a one-afternoon answer.
  3. Do cohesin-mutant and KMT2A-rearranged leukaemias ever co-occur, and if the non-synthetic-lethality argument is right that both act through HOXA, should we expect co-occurrence at exactly chance frequency? That is a quantitative prediction nobody has stated or tested.
Every source behind this entry (5)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    SMC1A is UniProt Q14683, structural maintenance of chromosomes protein 1A, 1233 residues, primary gene name SMC1A with synonyms DXS423E, KIAA0178, SB1.8, SMC1 and SMC1L1.

    What this evidence cannot show

    A naming fact. gene_exact:SMC1A AND organism_id:9606 AND reviewed:true returned exactly one row with gene_primary SMC1A. The synonym list includes the bare symbol SMC1, which is also historically used for the SMC1B meiotic paralogue - a real collision in older literature.

    Evidence that argues against this (1)
    • SMC3 at 1217 aa is only 16 residues shorter than SMC1A's 1233, the tightest paralogue-length pairing in this beat. A length check, which is the defence this project's Rule 65 prescribes, is nearly useless here; the accession is the only discriminator, exactly as for the histone variants. UniProt Consortium 2026
  2. E2moderate 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 SMC1A returns 11 records, and title-checking every one finds none about KMT2A-rearranged leukaemia; seven are Cornelia de Lange syndrome or related developmental-genetics studies, and the remainder are a lineage-switch case report, a paediatric AML miR-196b prognosis study, a short-stature gene-panel study and a microcephaly genomic analysis.

    What this evidence cannot show

    A counted absence, and its value is entirely in the symbol set. Aliases considered: SMC1, SMC1L1, SB1.8, DXS423E. SMC1 was deliberately NOT run bare because it is a prefix of SMC1A and SMC1B and collides with the SMC family. The complex form was run (see E3) and it changed the answer at the complex level while leaving the subunit-level absence standing. The graph's own bibliography was grepped for SMC1A, as Rule 64's second failure mode requires, and the grep CORRECTED a first draft of this caveat. SMC1A appears in four existing entries: in the effectors list of mechanism-loop-anchor-dsb-hotspots and in the gene list of genome-cohesin-architectural-colesion (both as part of 'cohesin', not cited to anything SMC1A-specific), and substantively in cell-state-pro-b-arrest and risk-lineage-switch-cd19-directed-therapy, which both cite PMID 42591212 - a case report in which TP53 and SMC1A mutations newly emerged at a B-ALL-to-AML lineage switch. That case report is the FIRST hit of the SMC1A query here and was title-checked as off-beat; reading its abstract confirms it, because the authors state explicitly that their case is a NON-KMT2A-rearranged leukaemia and frame the whole paper around lineage switch in cases without KMT2A rearrangement. So the absence stands, but it stands after the grep rather than before it.

    Evidence that argues against this (1)
    • An absence at the subunit symbol is exactly the failure mode Rule 64 was written for, and the check performed here is why the absence can be trusted rather than being another confident wrong count: running the complex form surfaced a KMT2A-specific cohesin paper reachable from no subunit symbol at all. Meyer A et al. 2024
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.preprint

    Running the complex form '(MLL OR KMT2A) AND cohesin' returns 17 records and surfaces a study of cohesin loss against an MLL fusion - complete Stag2 loss and Smc3 haploinsufficiency well tolerated in MLL-AF9-expressing murine HSPCs, concluding the two are not synthetic lethal - which is unreachable from the SMC1A, SMC3 or RAD21 symbol queries.

    PMID 38352423DOI
    What this evidence cannot show

    A preprint read from its abstract, murine, in-vitro self-renewal endpoint, and its perturbations are Stag2 and Smc3 rather than SMC1A. It establishes that the complex has KMT2A-specific literature; it does not establish anything about SMC1A.

    Evidence that argues against this (1)
    • The complex form has its own documented failure mode - ordinary-word contamination - and 'cohesin' is safe from that where 'FACT', 'SEC' and 'Mediator' are not, so the 17 records were readable. But four of the seventeen were on beat and the rest were Cornelia de Lange, which means even the complex form here is dominated by the cohesinopathy literature. Jann JC et al. 2024
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In 790 cohesin-mutant myeloid-malignancy patients, SMC1A mutations group with RAD21 and SMC3 as sharing features with de novo AML, better prognosis and co-occurrence with de novo AML-type lesions, in contrast to STAG2.

    Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes. · Jann JC, Hergott CB, Winkler M, Liu Y, Braun B, Charles A, et al. · Leukemia 2024
    PMID 39033241DOI
    What this evidence cannot show

    Adult retrospective two-centre cohort; KMT2A rearrangement is not a stratifying variable and this is the closest thing to SMC1A disease evidence in the beat, which is to say it is not about this disease at all. It is cited so the entry is not evidence-free, and its irrelevance to KMT2A-rearranged leukaemia is the point being made.

    Evidence that argues against this (1)
    • This is a co-mutation-pattern observation in adult myeloid malignancy. Reading it as SMC1A biology, or transferring it to infant KMT2A-rearranged disease, would be two unjustified steps - and the entry's whole purpose is to avoid exactly those steps. Mullenders J et al. 2015
  5. E5weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    In a case of lineage switch from B-precursor ALL to AML after inotuzumab ozogamicin, TP53 and SMC1A mutations newly emerged at switch while only a subset of ALL-relapse mutations was retained, which the authors read as selective expansion of a genetically distinct subclone; the report is explicitly about a leukaemia WITHOUT KMT2A rearrangement.

    PMID 42591212DOI
    What this evidence cannot show

    A single case report, targeted NGS, adult, and explicitly non-KMT2A-rearranged. It is recorded here because it is the only SMC1A-specific datum anywhere near this disease and because this graph already cites it twice - so a reader who greps for SMC1A will find it and should find the reason it does not support an SMC1A claim in KMT2A-rearranged leukaemia.

    Evidence that argues against this (1)
    • Lineage switch is a phenomenon this graph associates strongly WITH KMT2A rearrangement, which makes a non-KMT2A lineage-switch case an argument that the mechanism is not fusion-specific rather than an argument about SMC1A. Reading a new SMC1A mutation at switch as cohesin biology in KMT2A-rearranged disease would be two unsupported steps. Thol F et al. 2014
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