Oncofusion

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Proteinweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q74-interactome-gap

RPRM (reprimo) - the other half of menin's Ewing 2007 pair, a protein with no experimental localisation at all, and a promoter methylated in 45% of paediatric AML

also called RPRM · reprimo · Protein reprimo · Q9NS64

Reprimo is a very small protein thought to help p53 stop the cell cycle, and its gene is switched off by DNA methylation in nearly half of children with acute myeloid leukaemia. It was also pulled down once with menin in a large screen, and that single pull-down is the only physical link to this graph's central protein.

The same thing, for a scientist

RPRM (UniProt **Q9NS64, 109 aa**, primary gene name read back, no synonyms) is the only one of this beat's nine partners fished by **MEN1**, and it is the second and last of menin's two partners in Ewing et al. 2007 - the other being EBF3, which this graph already carries as `gene-ebf3` [E1][E2]. The interaction evidence is **one row**: MEN1 as FLAG-tagged bait, RPRM as prey, anti-bait co-immunoprecipitation in HEK293, interaction type `physical association`, **not spoke-expanded**, and IntAct carries the curated author annotation *"Number of different experiments interaction was observed in: 1"* alongside `author score: 0.4`, `author score: high` and an MI-score of 0.40 [E1]. **Two things make this weaker than it looks and one makes it more interesting than the other eight.** Weaker: RPRM's entire UniProt record is non-experimental - function `By similarity` (ECO:0000250), Cytoplasm (ECO:0000250), Membrane (ECO:0000305) - so **there is no experimentally supported localisation for this protein at all**, and menin is experimentally nuclear (ECO:0000269) [E3]. And `(RPRM[tiab] OR reprimo[tiab]) AND (menin[tiab] OR MEN1[tiab])` returns **0**, nineteen years after the screen [E4]. More interesting: **RPRM has a real, focused, paediatric leukaemia literature that has nothing to do with menin.** Tao et al. 2015 report RPRM promoter hypermethylation in 8 of 11 leukaemia cell lines and **44.8% (47/105) of paediatric AML samples against 6.7% (2/30) of controls**, with worse survival in methylated cases and reduced proliferation plus increased apoptosis on lentiviral RPRM re-expression [E5]. **So RPRM is the one partner in this beat whose disease context is paediatric acute leukaemia**, and the entry is written `weak` on the interaction and `moderate` on the epigenetic silencing, which are two different claims that should not be merged.

What it looks like
loading AF-Q9NS64-F1…
AlphaFold AF-Q9NS64-F1 ↗
colourshape

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

very high (90+)confident (70–90)low (50–70)very low (<50)
I have never read one of these pictures before

A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.

Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.

Anything in yellow sticks is a bound small molecule, which is usually the drug.

Go deeper
What the menin row is, and the one respect in which it is better than an atlas row

Ewing et al. 2007 immunoprecipitated 338 FLAG-tagged bait proteins and identified partners by LC-ESI-MS/MS, filtering 24,540 potential interactions to 6,463 among 2,235 proteins 2. It is a large-scale map and the provenance caveat that governs this whole beat applies.

But the bait list was not the proteome. The authors state the 338 baits were "selected based on known or suspected disease and functional associations". MEN1 was chosen. That is a weaker form of directedness than a study of menin, and a stronger one than an ORFeome-scale screen in which every protein is a bait by construction - which is the distinction the cycle-34 grading was reaching for and could not make.

It also matters that this row is not spoke-expanded. IntAct's expansion column reads -, meaning the pair was curated as a pair rather than inferred by binarising a complex against its bait. Four of the other eight partners in this beat are spoke expansions.

Against that: one experiment, one laboratory, 2007, HEK293 kidney cells, no reciprocal pulldown, no region, no affinity, no structure, and no follow-up in nineteen years. IntAct's own author-score annotation records the observation count as one.

A protein with no experimental annotation, which is a statement about the field and not about the protein

Reading the evidence codes as brief rule 91 requires:

RPRM  Q9NS64  109 aa
  FUNCTION  ECO:0000250  "May be involved in ... p53-dependent G2 arrest ...
                          Seems to induce cell cycle arrest by inhibiting CDK1
                          activity and nuclear translocation of the CDC2 cyclin B1
                          complex (By similarity)"
  LOCATION  ECO:0000250  Cytoplasm
  LOCATION  ECO:0000305  Membrane

Every statement is inferred. ECO:0000250 is homology-based inference and ECO:0000305 is curator inference; neither is an experiment. The hedging in the text - may, seems, By similarity - is UniProt's own.

This is the same shape Q71 flagged for SMARCD2, where a BAF subunit's nuclear call rested only on ECO:0000305. Here it is worse: there is no experimentally coded localisation of any kind. So the compartment argument that discounts TRAF2, GOLGA2, MTUS2 and LRRK2 in this beat cannot be run on RPRM - not because RPRM is nuclear, but because nobody has established where it is.

The honest consequence is that RPRM's menin row is unevaluable on compartment rather than refuted on it, and that a single immunofluorescence experiment on a 109-residue protein would be a disproportionately large addition to what is known about it.

The paediatric AML methylation result, kept separate on purpose

Tao et al. 2015 is a focused study in the right disease population and it says nothing about menin 5. Its content: RPRM promoter hypermethylation in 8/11 leukaemia lines and 44.8% of 105 paediatric AML samples versus 6.7% of 30 controls; bisulfite sequencing showing 66.2-83.1% methylation in AML against 20.0-27.7% in normal marrow; worse Kaplan-Meier survival with methylation; and functional rescue - lentiviral RPRM overexpression reduces proliferation dose-dependently and increases apoptosis.

Why it is kept in its own section rather than fused with the interaction. Merging them would produce the sentence "menin binds a tumour suppressor silenced in paediatric AML", which is two weakly connected facts wearing one confident clause. This project's documented failure mode is exactly that motion. The two claims share a protein and nothing else: the methylation work uses no menin reagent, and the menin pulldown used HEK293 cells.

The system caveat also runs the wrong way for this graph: paediatric AML, not infant B-lineage KMT2A::AFF1, and the abstract reports no KMT2A-rearranged subgroup. This graph's index disease is a B-lineage one and it has a documented history of importing myeloid results across that boundary.

What would join them is small and has never been done: is RPRM methylated in KMT2A-rearranged B-ALL, and does menin inhibition move it?

Facts and figures
uniprotQ9NS64
gene symbolRPRM
length AA109
alphafold IDAF-Q9NS64-F1
protein classsmall single-pass glycoprotein; candidate p53-dependent G2 arrest mediator
uniprot resolutiongene_exact:RPRM AND organism_id:9606 AND reviewed:true returned ONE reviewed row on 2026-09-21; primary gene name read back as RPRM; entry RPRM_HUMAN; 109 aa; no gene synonyms. Re-checked with gene:RPRM (synonym-inclusive) - still one record, so no collision.
localizationNONE ESTABLISHED. UniProt gives Cytoplasm (ECO:0000250, by similarity) and Membrane (ECO:0000305, curator inference). There is no experimentally coded subcellular localisation for RPRM. Retrieved 2026-09-21.
localization evidence codeECO:0000250 and ECO:0000305 only - no ECO:0000269 anywhere on the record
domains noteNo domain boundaries asserted. RPRM is 109 residues with no annotated domain architecture read back this cycle.
shown for fusionNobody has looked in any fusion. The menin pulldown is wild-type MEN1 in HEK293; there is no RPRM experiment in any KMT2A fusion or in any KMT2A-rearranged cell. The paediatric AML methylation work reports no KMT2A-rearranged subgroup.
domains
[]
interaction with the core complex
{
  "partner": "MEN1",
  "partner_accession": "O00255",
  "our_protein_role": "prey",
  "bait": "MEN1 (FLAG-tagged)",
  "method": "psi-mi:\"MI:0006\"(anti bait coimmunoprecipitation)",
  "interaction_type": "psi-mi:\"MI:0915\"(physical association)",
  "expansion": "none - curated as a pair, NOT spoke-expanded",
  "host_system": "Homo sapiens HEK293 embryonic kidney cell",
  "source_publications": [
    "17353931"
  ],
  "distinct_experiments": 1,
  "curated_observation_count": "author score: 'Number of different experiments interaction was observed in: 1'",
  "source_class": "338-bait disease-motivated AP-MS screen (not proteome-scale, not a study of menin)",
  "intact_acs": [
    "intact:EBI-1072454"
  ],
  "intact_miscore": 0.4,
  "other_men1_partners_in_the_same_publication": [
    "EBF3"
  ],
  "reciprocal_pulldown": false,
  "region_mapped": false,
  "affinity_measured": false,
  "structures": []
}
promiscuity controls 2026 09 21
{
  "distinct_partners_in_ewing_2007": 6,
  "distinct_partners_in_bioplex_3_0": 12,
  "distinct_partners_in_huri_luck_2020": 76,
  "distinct_partners_in_rolland_2014": 2,
  "distinct_partners_all_of_intact": 94,
  "note": "RPRM is a low-degree prey in the AP-MS datasets and a moderate hub in HuRI 2020 two-hybrid. Its degree does not explain the menin row."
}
counted absences
{
  "menin": {
    "query": "(RPRM[tiab] OR reprimo[tiab]) AND (menin[tiab] OR MEN1[tiab])",
    "records": 0
  },
  "leukaemia": {
    "query": "(RPRM[tiab] OR reprimo[tiab]) AND (leukemia[tiab] OR leukaemia[tiab])",
    "records_raw": 3,
    "records_on_topic": 1,
    "on_topic_pmid": "25629980",
    "off_beat_pmids": [
      "34211824",
      "24390737"
    ]
  },
  "operand_controls": {
    "RPRM[tiab]": 65,
    "reprimo[tiab]": 73,
    "union": 112
  },
  "aliases_searched": [
    "RPRM",
    "reprimo"
  ],
  "not_searched": "the RPRM family framing (RPRML, RPRM2)",
  "date": "2026-09-21",
  "bound": "zero in titles and abstracts over both spellings; supporting figures not searched; family-level framing not searched"
}
disease context that did not come from the interactome
{
  "claim": "RPRM promoter hypermethylation in 44.8% of 105 paediatric AML samples versus 6.7% of 30 controls, worse survival with methylation, and anti-proliferative plus pro-apoptotic effect of RPRM re-expression",
  "pmid": "25629980",
  "lineage": "paediatric AML - myeloid, no KMT2A-rearranged subgroup reported",
  "relation_to_the_menin_row": "none. The two facts share a protein and no reagent, cell type or experiment. They are recorded separately on purpose."
}
How this could bite us back
  • Nothing in this entry supports an intervention. If anything the epigenetic result points the wrong way for a drug: RPRM is silenced in AML and its re-expression is anti-proliferative, so the therapeutic move would be demethylation rather than inhibition - and hypomethylating agents are non-specific, so a RPRM-framed rationale for azacitidine in this disease would be a rationale for a drug that changes thousands of promoters.
  • If menin genuinely binds RPRM, menin inhibition could release or redirect a p53-pathway component, which is an off-mechanism effect of the graph's central drug class that nobody is measuring. That is speculative on a single 2007 row and is written here as a thing to watch, not a prediction.
Still open
  1. Is the RPRM promoter methylated in KMT2A-rearranged B-ALL as it is in paediatric AML, and does menin inhibition change it? This is the one experiment that would join the two halves of this entry, it uses material this field already has, and nobody has run it.
  2. Where is RPRM in a cell? There is no experimentally coded localisation for this protein anywhere in UniProt. A 109-residue protein with a published tumour-suppressor phenotype and no established compartment is an unusually cheap gap to close, and until it is closed the menin interaction cannot be assessed on compartment in either direction.
  3. Does the menin-RPRM pulldown reproduce? Nineteen years, zero follow-up publications, and IntAct's own curation records it as observed in one experiment. A single endogenous co-IP in a leukaemia line would retire it or promote it.
Every source behind this entry (5)
  1. E1weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.database

    IntAct records a single MEN1-RPRM row, from PMID 17353931, anti-bait coimmunoprecipitation with MEN1 as bait in HEK293, interaction type physical association, no spoke expansion, MI-score 0.40, carrying the curated author annotation 'Number of different experiments interaction was observed in: 1'; MEN1's only other partner in that publication is EBF3.

    What this evidence cannot show

    One row, one publication, one experiment by the curators' own annotation, 2007, HEK293 kidney cells, no reciprocal pulldown, no region, affinity or structure, and no follow-up since. The MI-score of 0.40 is the second lowest in this beat. The absence of spoke expansion is a genuine but small advantage over four of the other eight partners here.

    Evidence that argues against this (1)
    • This graph's own menin-interactome enumeration already treats single rows from this publication as hypothesis-generating rather than established, and gene-ebf3 - the only other MEN1 partner from the same screen - is graded weak on exactly this basis. RPRM should not be graded higher than its sibling row. Oncofusion knowledge graph, gene-ebf3 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Ewing et al. 2007 immunoprecipitated 338 FLAG-tagged bait proteins selected on known or suspected disease and functional associations, identified partners by LC-ESI-MS/MS, and filtered 24,540 potential interactions to a dataset of 6,463 interactions among 2,235 proteins.

    Large-scale mapping of human protein-protein interactions by mass spectrometry. · Ewing RM, Chu P, Elisma F, et al., Figeys D · Mol Syst Biol 2007
    PMID 17353931DOI
    What this evidence cannot show

    Read as abstract, not full text. This is a large-scale map and the authors describe the output as a source of novel interactions with relevance to human disease - hypothesis-generating by their own framing. The bait selection was disease-motivated rather than proteome-wide, which makes it less of a pure atlas than BioPlex or HuRI, but it is still one screen reporting thousands of pairs. Already cited twice in this graph.

    Evidence that argues against this (1)
    • A screen that filters 24,540 candidates to 6,463 by empirical criteria and a confidence score is accepting a false-positive rate by design, and a single unreplicated pair sits wherever that threshold put it. The curated note that this interaction was observed in one experiment places it at the bottom of that distribution rather than in its body. Huttlin EL et al. 2021
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    RPRM is UniProt Q9NS64, 109 aa, primary gene name RPRM with no synonyms, recommended name Protein reprimo; every annotation on the record is non-experimental - the function comment is ECO:0000250 (by similarity), Cytoplasm is ECO:0000250 and Membrane is ECO:0000305 - so there is no experimentally coded subcellular localisation for this protein, while MEN1 is annotated Nucleus with ECO:0000269.

    What this evidence cannot show

    Retrieved 2026-09-21 with evidence codes read, per brief rule 91. ECO:0000250 is homology-based inference and ECO:0000305 is curator inference; neither is an experiment, and UniProt's own wording hedges throughout ('May be involved', 'Seems to induce', 'By similarity'). gene:RPRM AND organism_id:9606 AND reviewed:true returns exactly one reviewed record, so there is no paralogue collision - the dispatch brief flagged RPRM as collision-shaped and it is not.

    Evidence that argues against this (1)
    • An absence of experimental annotation says how much work has been done, not where the protein is. It means the compartment argument used against four other partners in this beat cannot be run here in either direction, which leaves the menin row unevaluable on compartment rather than supported. Tao YF et al. 2015
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    No literature connects RPRM to menin or MEN1: (RPRM[tiab] OR reprimo[tiab]) AND (menin[tiab] OR MEN1[tiab]) returns 0 records, nineteen years after the screen that reported the interaction.

    What this evidence cannot show

    Operand controls: RPRM[tiab] returns 65, reprimo[tiab] returns 73, the union query returns 112, and (RPRM OR reprimo) AND (leukemia OR leukaemia) returns 3 - so the instrument returns ones and both spellings are live and non-identical. Querytranslation expanded as written. 'MEN1' also denotes the multiple endocrine neoplasia syndrome, which would inflate rather than deflate this count; it did not. Zero in titles and abstracts; supporting figures not searched.

    Evidence that argues against this (1)
    • 'Reprimo' is a short word-like token with a family - RPRML and RPRM2 exist - and a query over the parent symbol will miss work framed on the family. This project has recorded a false absence from exactly that shape, and the family-level phrase was not searched here. Ewing RM et al. 2007
  5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In paediatric acute myeloid leukaemia, the RPRM promoter is hypermethylated in 8 of 11 leukaemia cell lines and in 44.8% (47/105) of patient samples against 6.7% (2/30) of controls, methylation is associated with worse Kaplan-Meier survival, and lentiviral RPRM overexpression inhibits AML cell proliferation dose-dependently and increases apoptosis.

    PMID 25629980DOI
    What this evidence cannot show

    Paediatric AML, not infant B-lineage KMT2A::AFF1 - a myeloid cohort, and the abstract reports no KMT2A-rearranged subgroup and no lineage breakdown. Read as abstract, not full text. Single centre, single publication, n = 105 cases against 30 controls, and the survival analysis is univariate Kaplan-Meier with no multivariable adjustment reported in the abstract. Overexpression of a candidate tumour suppressor reducing proliferation is a low-specificity readout. New to this graph. Nothing in this item involves menin.

    Evidence that argues against this (1)
    • Promoter hypermethylation of a CpG-island gene in leukaemia is extremely common and is frequently a passenger of the global methylation changes in the disease rather than a driver; a 45%-versus-7% contrast establishes association, and the overexpression rescue is done in cells that were already methylated rather than in a model where methylation is the manipulated variable. Qi H et al. 2021
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