The H3K27me3 absence this graph keeps asserting is narrower than stated: the measurement exists, in the genetic arm of the paper the graph cites for the phenocopy
also called H3K27me3 menin inhibitor absence · menin polycomb measurement gap
This project has been saying that nobody has ever measured the silencing mark H3K27me3 in a cell treated with a menin drug. That is very nearly right and not exactly right: the measurement exists, in the same paper the project already cites, but in cells where the menin gene was deleted rather than drugged.
The same thing, for a scientist
Two entries in this graph assert, without a query, that **no menin-inhibitor study in any system reports an H3K27me3 measurement**. Read as written it is false. **Sparbier et al. 2023** - the paper this graph cites for menin inhibition phenocopying polycomb disruption - performed **H3K27me3 CUT&Tag in MEN1-knockout versus control cells**, reporting **total H3K27me3 unchanged** and, at bivalent non-Menin-bound promoters, **increased H3K4me3 with reduced H3K27me3 and SUZ12 occupancy** [E2]. The paper's **VTP50469 arm carries Menin ChIP-seq and RNA-seq and no H3K27me3** [E2], and its hESC menin-inhibitor analysis **integrates pre-existing public H3K4me3/H3K27me3 ChIP-seq (GSE96336, GSE96353) rather than generating it** [E2]. So the defensible claim is the narrow one: **no H3K27me3 measurement under a menin INHIBITOR has been reported in any system** [E1]. The genetic arm already exists and already constrains the answer.
How the wrong version survived, and it was a name list
The first query run to test the claim looked correct and returned a clean zero:
(menin inhibitor OR revumenib OR ziftomenib OR VTP-50469 OR MI-503 OR MI-538 OR MI-2-2)[tiab] AND H3K27me3[tiab] -> 0
The positive controls through the identical shape passed - the same drug clause returns 6 with H3K4me3 and 2 with H3K79 - so by brief rule 67 the zero was interpretable. It was still wrong, and the reason is the name list, not the query mechanics:
| added string | count |
|---|---|
VTP-50469 (hyphenated, as written above) | 0 |
VTP50469 (unhyphenated, as the paper writes it) | still 0 in abstracts |
"menin inhibition" and "menin inhibitors" | 2 |
The plural and the nominalisation were the whole difference. "menin inhibitor"[tiab] is an unstemmed phrase; inhibitors and inhibition are different queries, exactly as the brief's septin section records for singular versus plural. This is rule 70's lesson - the name list is the instrument - arriving on a drug class rather than on a noncoding element.
The broader operand check settles it independently: menin[tiab] AND H3K27me3[tiab] returns 8, of which 4 are leukaemia- or MLL-context 1. A claim that nobody has measured H3K27me3 near menin could have been falsified by the simplest possible query, which nobody ran.
What the genetic measurement actually says, and why it is not a substitute
From the full text 2:
- "we profiled H3K4me3, H3K27me3 and SUZ12 chromatin occupancy in control and MEN1 knockout cells"
- "Total levels of H3K4me3, H3K27me3, H2AK119Ub, SUZ12 and EZH2 were unchanged following MEN1 knockout"
- "At bivalent non-Menin-bound promoters, we observed increased H3K4me3 and reduced H3K27me3 and SUZ12 occupancy following MEN1 knockout"
That is already a partial answer to the question exp-menin-inhibitor-h3k27me3-timecourse-index-fusion was designed to ask, and it points between that entry's two routes: global H3K27me3 is not lost (against a simple Route 1 in which menin loss lowers EZH2 and therefore the mark), while locus-level H3K27me3 does fall at a defined promoter class (against a pure Route 2 in which PRC2 occupancy is intact).
It is not a substitute for the drug experiment, for three stated reasons: the system is K-562, not a KMT2A-rearranged B-lineage blast; genetic knockout removes menin protein entirely while an inhibitor displaces it from a motif and leaves the protein present, which is exactly the distinction 3 draws when Men1 deletion and the compounds give distinct consequences; and a knockout is a chronic state where an inhibitor timecourse is what the ordering question needs.
The correction owed, stated to the standard this graph requires
Entries affected (not edited by this beat - reported):
exp-menin-inhibitor-h3k27me3-timecourse-index-fusion, fielddata.why_not_done: "No menin-inhibitor study in any system reports an H3K27me3 measurement, despite the menin-EZH2 link being in print since 2013..." and the equivalent sentence insummary_expert("currently indistinguishable in every published one, because no menin-inhibitor study in any system reports H3K27me3"). Should say: no H3K27me3 measurement under a menin inhibitor has been reported; H3K27me3 CUT&Tag in MEN1-knockout versus control cells is reported in PMID 36635503, with total levels unchanged and occupancy reduced at bivalent non-Menin-bound promoters, and that result already constrains the entry's own decision rule.- Any sibling entry repeating the unqualified sentence -
mechanism-menin-inhibition-shifts-the-kmt2a-polycomb-balancecites the same paper and should carry the genetic result explicitly rather than only the phenocopy headline.
Citation that settles it: PMID 36635503, DOI 10.1038/s41556-022-01056-x. Full text read, not only the abstract - Europe PMC fullTextXML on PMC7614190, 113,400 characters, retrieved 2026-09-20. The abstract alone does not settle it, which is why the unqualified claim was survivable for as long as it was.
Correction 2026-09-20: the absence narrows a SECOND time
This entry's narrowed claim - no H3K27me3 measurement under a pharmacological menin inhibitor - is also false. PMID 38173411 treated human adipose-derived stem cell spheroids with 70 uM SNDX-5613 (revumenib) and blotted H3K27me3: "had no effect on H3K27me3".
The defensible statement is now: no locus-resolved H3K27me3 measurement under a pharmacological menin inhibitor has been reported in a KMT2A-rearranged leukaemia; one bulk Western blot exists, in a non-leukaemic system, and it was negative. Full reasoning and the bounded query in ana-the-h3k27me3-absence-narrows-a-second-time.
| claim corrected | No menin-inhibitor study in any system reports an H3K27me3 measurement |
|---|---|
| corrected to | No H3K27me3 measurement under a menin INHIBITOR has been reported; H3K27me3 CUT&Tag under genetic MEN1 knockout is reported in PMID 36635503 |
| trap class | an unstemmed multi-word phrase: 'menin inhibitor', 'menin inhibitors' and 'menin inhibition' are three different queries |
| chain | mechanism-kmt2a-fusion-causal-chain |
entries affected not edited
[ "exp-menin-inhibitor-h3k27me3-timecourse-index-fusion", "mechanism-menin-inhibition-shifts-the-kmt2a-polycomb-balance" ]
settling citation
{
"pmid": "36635503",
"doi": "10.1038/s41556-022-01056-x",
"read": "full text via PMC7614190, 2026-09-20",
"title": "Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.",
"authors": "Sparbier CE, Gillespie A, Gomez J, et al.",
"venue": "Nat Cell Biol",
"year": 2023,
"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."
}genetic arm result
{
"total_h3k27me3_after_MEN1_KO": "unchanged",
"h3k27me3_occupancy_at_bivalent_non_menin_bound_promoters": "reduced",
"h3k4me3_at_same_promoters": "increased",
"suz12_at_same_promoters": "reduced",
"system": "K-562"
}pharmacological arm readouts
[ "Menin ChIP-seq", "RNA-seq" ]
strings tried
[ "menin inhibitor", "menin inhibitors", "menin inhibition", "revumenib", "ziftomenib", "bleximenib", "enzomenib", "VTP50469", "VTP-50469", "MI-503", "MI-538", "MI-2-2", "SNDX-5613", "KO-539", "menin", "MEN1" ]
counts — the numbers behind the chart
{
"drug_clause_AND_H3K27me3_first_list": 0,
"drug_clause_AND_H3K4me3_control": 6,
"drug_clause_AND_H3K79_control": 2,
"drug_clause_alone": 118,
"expanded_drug_clause_AND_H3K27me3": 2,
"menin_AND_H3K27me3": 8,
"menin_AND_H3K27me3_AND_leukaemia_or_MLL": 4
}- The correction weakens a design rationale rather than a therapy: `exp-menin-inhibitor-h3k27me3-timecourse-index-fusion` is still worth running, but it is now a replication-with-a-prediction rather than a first measurement, which changes how it should be pitched and funded.
- An entry that overstates an absence invites a reviewer to find the counterexample in one query, and this project's credibility rests disproportionately on its absence claims being the ones that hold.
- This entry's central absence claim has now been narrowed TWICE, on 2026-09-20 both times. Treat the remaining claim as provisional and re-run the bounded query before quoting it.
- Does H3K27me3 behave under a menin inhibitor as it does under MEN1 knockout - total unchanged, locus-level reduced at bivalent non-Menin-bound promoters? Nobody has run it, and the knockout result makes a specific prediction to test.
- How many other unqualified absence sentences in this graph were written without a query? This one carried a date, a mechanism and a decade-long grievance, and had no count attached to it anywhere.
- Does the K-562 result hold in a KMT2A-rearranged B-lineage blast, where the bivalent promoter set and the polycomb complement are both different?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
A drug-name query for menin inhibitors ANDed with H3K27me3 returns 0 on PubMed at 2026-09-20 while the identical shape returns 6 for H3K4me3 and 2 for H3K79; adding the strings 'menin inhibition' and 'menin inhibitors' raises the H3K27me3 count to 2, and the broader query menin AND H3K27me3 returns 8, of which 4 are leukaemia- or MLL-context.
PubMed E-utilities esearch, run 2026-09-20 by the Q52 spine beat; counts and querytranslation strings recorded verbatim · Oncofusion knowledge graph (internal measurement) 2026What this evidence cannot show
Counted and dated, with positive controls through the identical query shape. The finding is about the NAME LIST rather than the query mechanics: the seven-drug-name clause composes correctly and still produces a false negative. Strings tried are listed in data.strings_tried; not tried: trade names, 'MEN1 inhibitor', or any non-English phrasing. Title-checked: of the 2 records recovered, one (38173411) is an adipose-stem-cell paper and off topic, and one (34663924) profiles H3K27me3 and separately applies menin inhibitors without reporting the mark under the drug.
Evidence that argues against this (2)
- An abstract-level query cannot see a measurement reported only in a figure or in extended data, which is precisely how the decisive H3K27me3 CUT&Tag in this case is presented - so even the corrected count is an abstract-vocabulary measurement and not a statement about what has been measured. Sparbier CE et al. 2023
- SUPERSEDED 2026-09-20 (second narrowing). A pharmacological menin inhibitor HAS now been assayed against H3K27me3: PMID 38173411 treated human adipose-derived stem cells with 70 uM SNDX-5613 (revumenib) and reported by Western blot that it 'had no effect on H3K27me3'. The defensible statement is now narrower again - no LOCUS-RESOLVED H3K27me3 measurement under a pharmacological menin inhibitor in a KMT2A-REARRANGED LEUKAEMIA - and the single existing datapoint is negative, in a non-leukaemic system, by bulk blot. See [[ana-the-h3k27me3-absence-narrows-a-second-time]]. Chang MM et al. 2024
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Sparbier et al. profiled H3K4me3, H3K27me3 and SUZ12 chromatin occupancy in control and MEN1-knockout cells, finding total H3K4me3, H3K27me3, H2AK119Ub, SUZ12 and EZH2 unchanged after MEN1 knockout and, at bivalent non-Menin-bound promoters, increased H3K4me3 with reduced H3K27me3 and SUZ12 occupancy; the VTP50469 arm of the same study reports Menin ChIP-seq and RNA-seq without H3K27me3, and the hESC menin-inhibitor analysis integrates pre-existing public H3K4me3 and H3K27me3 ChIP-seq.
Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes. · Sparbier CE, Gillespie A, Gomez J, Kumari N, et al. · Nat Cell Biol 2023What this evidence cannot show
Full text read 2026-09-20 via Europe PMC fullTextXML on PMC7614190 (113,400 characters after tag-stripping then entity-unescaping, in that order per brief rule 61); quoted sentences taken from the Results and the Extended Data legends. The system is K-562 and human pluripotent stem cells, NOT a KMT2A-rearranged leukaemia, so the genetic result constrains the general menin-polycomb question and not the index disease.
Evidence that argues against this (1)
- Menin-inhibitor compounds engage menin-MLL1, menin-MLL2 and other menin interactions and Men1 deletion produces consequences distinct from Mll1;Mll2 co-deletion, so a genetic knockout result cannot be read straight across to the pharmacological arm - which is the reason the drug experiment is still owed. Chen Y et al. 2019
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Automated CUT&Tag profiling in KMT2A-rearranged leukaemia maps fusion-specific targets, finds a subset of oncofusion-binding sites carrying bivalent H3K4me3/H3K27me3 signatures with single-cell heterogeneity, and separately shows that aberrant gene-body H3K4me3 enrichment is sensitive to menin inhibitors.
Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia. · Janssens DH, Meers MP, Wu SJ, Babaeva E, et al. · Nat Genet 2021What this evidence cannot show
Abstract read 2026-09-20. This is the record that makes the naive query look answerable and is not the answer: the H3K27me3 profiling establishes bivalency at baseline, and the menin-inhibitor sensitivity is reported for H3K4me3. The abstract does not state that H3K27me3 was profiled in inhibitor-treated cells. Recorded here as the nearest existing measurement in the right disease.
Evidence that argues against this (1)
- Population-level bivalency calls cannot distinguish a bivalent nucleosome from a mixture of cells or alleles, which this paper's own single-cell data address for heterogeneity but not for the underlying nucleosome state - so 'bivalent sites exist in this disease' is itself a claim with a method caveat. Sparbier CE et al. 2023
THE FIRST NARROWING WAS NOT ENOUGH. That entry's surviving claim is also false.
the entry's why_not_done overstates the absence; the genetic measurement exists and constrains its decision rule
- supports →Trithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it
adds the genetic-arm H3K27me3 result from the paper that entry already cites
bounds break 3 of the chain - what the drug does that is not fusion biology
the only H3K27me3 measurement near menin, and it is genetic rather than pharmacological