Oncofusion

start / graph / interface-kmt2a-anos1-declined-a-secreted-protein-in-a-kidney-cell-lysate

Interfaceweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q129-the-never-discussed-partners-of-kmt2a-and-psip1

KMT2A-ANOS1 is one spoke-expanded BioPlex 3.0 AP-MS row with ANOS1 - a secreted, cell-membrane axon-guidance protein - as the bait and KMT2A as the prey in HEK293T - declined

also called KMT2A-ANOS1 · MLL-ANOS1 · anosmin-1 · KAL1 · EBI-54555827

A database lists anosmin-1, a protein cells secrete to guide growing nerve fibres, as a KMT2A partner. The single supporting experiment tagged anosmin-1 in kidney cells and found KMT2A in the catch, which is not a place a secreted protein and a chromatin enzyme can plausibly meet.

The same thing, for a scientist

**Verdict: DECLINED, on a compartment argument with an experimentally coded annotation behind it. Detection method is anti-tag co-immunoprecipitation (AP-MS) in BioPlex 3.0, spoke-expanded, with ANOS1 as bait and KMT2A as prey** [E1]. One IntAct record, EBI-54555827, PMID 33961781, HEK293T only, intact-miscore 0.35 [E1]. UniProt P23352 gives ANOS1 as 680 aa with subcellular location **Cell membrane [ECO:0000269] and Secreted [ECO:0000269]** and no nuclear annotation of any kind, tissue specificity 'expressed in the cerebellum (at protein level)' [E3]. Its function is branch-promotion and guidance of olfactory axons; loss-of-function causes X-linked Kallmann syndrome. **A secreted extracellular-matrix-associated protein and a 3,969-residue nuclear methyltransferase have no shared compartment**, and HEK293T is embryonic kidney, not a tissue that expresses ANOS1. Spoke expansion means the binary pair was never measured. **This row's real value to this project is as an internal negative control**: it sits at the same 0.35 floor score, in the same screen, as the nucleolar candidates ABT1 and KRR1 that the beat was dispatched to take seriously [E4].

Go deeper
Why this entry exists at all, given the verdict is obvious

An obviously impossible pair is worth writing down because it calibrates the ones that are not obvious.

BioPlex 3.0 recovered KMT2A as prey from 24 distinct baits. Three of them - WDR5, RBBP5, ASH2L - are the genuine WRAD core of the MLL1 complex and score 0.96, 0.95 and 0.91. Seventeen sit at the 0.35 floor 4. ANOS1 and FGFBP1, both experimentally annotated as secreted, are in that floor band, and so are ABT1 and KRR1, the nucleolar proteins this beat was sent to evaluate as possible real biology.

So the correct reading of a 0.35 BioPlex KMT2A row is not 'unproven'; it is 'in the band that contains pairs which cannot be physiological'. That is a statement about the band, and ANOS1 is the evidence for it.

The honest limit of the argument. The intact-miscore is IntAct's pair-level score, not BioPlex's per-experiment CompPASS-Plus probability, and the two are not the same quantity. It is entirely possible that BioPlex's own score separates KRR1 from ANOS1. That number is published on the BioPlex portal and was not retrieved here; retrieving it is the single cheapest way to strengthen or overturn this whole beat.

What would have to be true for the row to be real

Three things, none of which is recorded anywhere:

  1. An intracellular ANOS1 pool. UniProt has no nuclear or cytoplasmic comment for P23352 at any evidence level 3. Over-expression of a tagged secretory protein can saturate the secretory pathway and leave protein in the cytosol, but that is an artefact of the experiment, not a physiological pool.
  2. Co-expression. ANOS1's recorded tissue specificity is cerebellum at protein level; HEK293T is embryonic kidney 13. Neither the natural context of ANOS1 nor any haematopoietic cell was used.
  3. A measurement of the pair. The record is spoke-expanded, so no binary observation exists, and reciprocal confirmation is impossible because KMT2A is a prey-only node in BioPlex - all 31 BioPlex rows touching Q03164 have KMT2A as prey 1.
Facts and figures
partner agene-kmt2a
partner a uniprotQ03164
partner a length AA3969
partner bANOS1
partner b uniprotP23352
partner b length AA680
verdictDECLINED
adjudicated byQ129, cycle 92, 2026-09-23
source publication pmid33961781
source datasetBioPlex 3.0
detection methodanti-tag co-immunoprecipitation (AP-MS)
experimental role partnerbait
experimental role kmt2aprey
kmt2a was never the baittrue
expansion methodspoke expansion
intact miscore0.35
replicated in second bioplex linefalse
reciprocally confirmedfalse
reciprocal confirmation possiblefalse
n publications1
n methods1
orthogonal method existsfalse
role in this beatinternal negative control for the 0.35 BioPlex floor band
druggabilityNot assessable and not worth assessing; no residue or region is mapped and the pair is declined.
absence classnever-measured
absence class noteNo experiment has tested KMT2A against ANOS1 with KMT2A as the bait, in any cell. Given the compartment mismatch this is an absence nobody should close: the useful statement is that the existing row is uninterpretable, not that the experiment is owed.
shown for fusionNO - nobody has looked in any KMT2A fusion.
epigenetic readoutnone.
host cell lines
[
  "HEK293T embryonic kidney"
]
records
[
  "EBI-54555827"
]
compartment mismatch
{
  "partner_compartments": [
    "Cell membrane [ECO:0000269]",
    "Secreted [ECO:0000269]"
  ],
  "partner_nuclear_annotation": "none at any evidence level",
  "partner_tissue": "cerebellum (at protein level)",
  "host_line": "HEK293T embryonic kidney",
  "host_expresses_partner_natively": false
}
interface residues a
[]
structures
[]
ligands
[
  "drug-revumenib",
  "drug-ziftomenib"
]
How this could bite us back
  • This entry's main risk is over-generalisation in the opposite direction: if 'floor score plus compartment mismatch' becomes a reflex for discarding rows, a real low-abundance partner recovered once will be thrown away with the noise, and low-abundance nuclear partners are exactly what a menin-inhibitor resistance mechanism would look like.
  • Nothing here touches a therapeutic hypothesis directly, but the calibration does: several intervention proposals in this graph rest on single AP-MS rows, and the correct reading of the 0.35 band applies to them too.
Still open
  1. What CompPASS-Plus probability did BioPlex itself assign to ANOS1-KMT2A, and is it separable from the probability assigned to KRR1-KMT2A? If the authors' own score does not separate a secreted protein from a nucleolar one on the same prey, that is a finding about the dataset worth recording independently of this pair.
  2. How many other KMT2A partners in this graph rest on a single spoke-expanded row with a compartment mismatch? The question has never been asked corpus-wide.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    IntAct curates one record of a KMT2A-ANOS1 association, EBI-54555827, from PMID 33961781 (BioPlex 3.0), annotated to Supplementary table 1. Detection method anti-tag co-immunoprecipitation, interaction type 'association', expansion method SPOKE EXPANSION, host Homo sapiens HEK293T embryonic kidney cell. ANOS1 (P23352) is the BAIT and KMT2A (Q03164) is the PREY. intact-miscore 0.35. All 31 BioPlex rows touching Q03164 have KMT2A as prey, so KMT2A is a prey-only node in that dataset and reciprocal confirmation is not available.

    What this evidence cannot show

    Read live from IntAct REST on 2026-09-23, not PSICQUIC (rule 93). The BioPlex supplementary table was not opened, so the row rests on IntAct's curation. Spoke expansion is the decisive field: the binary KMT2A-ANOS1 pair was never observed, it was inferred by connecting every prey in an ANOS1 pull-down to the bait.

    Evidence that argues against this (1)
    • IntAct records this row honestly, with the expansion method in the row itself. The defect being described is in how such rows get consumed downstream - as binary interactions - not in the curation. Any reader who reaches the expansionMethod field is not misled. IntAct (EMBL-EBI) 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In human HEK293T and HCT116 epithelial cell lines, BioPlex 3.0 affinity-purified 10,128 tagged human proteins giving 118,162 interactions among 14,586 proteins, plus 5,522 immunoprecipitations in HCT116, scored by CompPASS-Plus against a GFP control at 1% protein-level FDR with entropy-based dataset-level filtering, and states that about 60% of interactions in both networks are confirmed by replication, reciprocal recovery or co-fractionation.

    Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. · Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, et al. (28 authors), Gygi SP · Cell 2021
    PMID 33961781DOI
    What this evidence cannot show

    Full text read 2026-09-23 through the PMC HTML route (PMC8165030) after Europe PMC fullTextXML returned HTTP 500. Neither 'KMT2A' nor 'ANOS1' appears in the paper's text; the row is a supplementary-table entry that was not opened here. So the paper does not report this interaction in prose.

    Evidence that argues against this (1)
    • BioPlex recovered the genuine MLL1 complex on KMT2A at 0.91-0.96, so the dataset is not being dismissed. The objection is specific to floor-score rows whose partner has no compatible compartment. IntAct (EMBL-EBI) 2026
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB P23352 is 680 aa, primary gene name ANOS1, recommended name 'Anosmin-1'. Its only subcellular-location comments are Cell membrane [ECO:0000269] and Secreted [ECO:0000269]; there is no nuclear or cytoplasmic comment at any evidence level. Function: dual branch-promoting and guidance activity for mitral and tufted cell collaterals to the olfactory cortex, and chemoattractant for fetal olfactory epithelial cells. Tissue specificity: expressed in the cerebellum (at protein level).

    What this evidence cannot show

    UniProt location comments are curated pointers, not measurements (rule 91), and the cited localisation papers were not opened. The absence of a nuclear comment is an absence in UniProt's record, not a published negative - nobody has reported looking for nuclear anosmin-1 and failing to find it, as far as this beat searched, and no PubMed query was run on that question.

    Evidence that argues against this (1)
    • Secreted and matrix proteins do occasionally have documented nuclear pools, and an argument from UniProt compartments is an argument from an incomplete record - UniProt's own KMT2A entry leaves two of its three location comments uncoded. The decline here rests on the conjunction of compartment, wrong tissue, spoke expansion and floor score, not on compartment alone. UniProt Consortium 2026
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Among the 24 distinct BioPlex 3.0 baits that recover KMT2A as prey, the intact-miscores are WDR5 0.96, RBBP5 0.95, ASH2L 0.91, CSNK2A2 0.79, CSNK2B 0.64, HCFC2 0.62, CSNK2A1 0.53, and 0.35 for the other seventeen - a band that contains ANOS1 and FGFBP1, both experimentally annotated as secreted, alongside the nucleolar proteins ABT1 and KRR1 and the ribosomal proteins RPL36, RPLP0, RPS9 and Rpl13a.

    What this evidence cannot show

    intact-miscore is a pair-level score driven mainly by the number of supporting publications and methods, so the 0.35 band is close to a restatement of 'one record of one kind'. It is not BioPlex's own per-experiment confidence, which was not retrieved. Using ANOS1 as a negative control therefore calibrates IntAct's aggregate score, not the source screen's internal statistics.

    Evidence that argues against this (1)
    • The floor band also contains SET, a real histone chaperone and nucleosome-assembly protein whose association with a chromatin methyltransferase would not be surprising. So the band is not uniformly false, and calling it 'the band that contains impossible pairs' is a statement about its lower bound rather than about every member. IntAct (EMBL-EBI) 2026
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