LEDGF occupancy under revumenib: the measurement the graph called missing exists, in one 2025 preprint, and it goes the way the tenfold cooperativity predicts
also called LEDGF chromatin binding under SNDX-5613 · cooperative clamp under menin inhibition
Menin makes the leukaemia protein grip LEDGF about ten times more tightly, so blocking menin should loosen the LEDGF grip too. A 2025 preprint measured it: giving the menin drug revumenib does reduce how much LEDGF sits on the leukaemia's target genes.
The same thing, for a scientist
The structural interface beat established that the LEDGF IBD binds MLL 1-160 at Kd 14.7 uM alone and the preformed menin-MLL complex at 1.4 uM - an approximately tenfold cooperative enhancement - and recorded that nobody had measured what happens to LEDGF occupancy when a menin inhibitor evicts menin. **That absence is now only partly true.** A 2025 bioRxiv preprint (PMID 41279447) profiled LEDGF by CUT&RUN in MOLM-13 (KMT2A::MLLT3) and MV4-11 (KMT2A::AFF1) under the clinical menin inhibitor SNDX-5613 (revumenib) and reports that *'Menin blockade with SNDX-5613 further decreased MLL and LEDGF chromatin binding'*. The direction matches the cooperativity prediction and therefore favours **menin primacy**: without menin the LEDGF grip is roughly ten times weaker, and the occupancy follows. Three things stop this closing the question. It is a **preprint**. The comparison is embedded in a menin-plus-LSD1 combination study in which the LSD1 inhibitor ORY-1001 **alone** reduced MLL and LEDGF occupancy to a degree the authors call comparable to menin inhibition, so the menin arm is not the study's focus. And the effect is reported from metaplots and representative tracks without a quantified occupancy change or a dose-response.
What the preprint reports, in its own terms
From the results section, on the CUT&RUN panel at FLT3-PAN3, CDK6, the HOX cluster, MEIS1 and PBX3 1:
'treatment with the LSD1 inhibitor ORY-1001 alone unexpectedly reduced MLL and LEDGF occupancy and diminished H3K36me3, to a degree comparable to menin inhibition. Menin blockade with SNDX-5613 further decreased MLL and LEDGF chromatin binding, and the combination exacerbated these effects, culminating in near-complete eviction of H3K36me3 from LEDGF-bound loci.'
And on the reciprocal:
'Menin occupancy was selectively reduced by menin inhibition, with little to no change between DMSO and LSD1 inhibition, and no appreciable further decrease upon combination treatment.'
The LEDGF antibody is named in the methods (Bethyl A300-848A), the CUT&RUN uses pAG-MNase with E. coli spike-in normalisation, and the cell lines are MOLM-13 and MV4-11. MV4-11 carries t(4;11)/KMT2A::AFF1, so a human KMT2A::AFF1 model is in the dataset, in a myeloid context (line-mv4-11-kmt2a-aff1-myeloid).
Two readings, and which this favours
The cycle-17 king log set the question up as a fork:
- Reading A, menin primacy. Menin eviction costs the fusion a tenfold LEDGF affinity enhancement, LEDGF occupancy falls, and the LEDGF axis is largely downstream of the drug the clinic already has. A LEDGF agent then adds little to a menin inhibitor in menin-inhibitor-sensitive disease.
- Reading B, residual grip. LEDGF occupancy survives menin eviction, keeps the fusion addressed, and explains non-genetic escape. A LEDGF agent is then the natural partner or successor.
The measurement favours A. That is the less convenient answer for the LEDGF programme and it should be stated as such.
But A is not established by it, for a reason internal to the data: the causal route is ambiguous. LEDGF occupancy could fall because the cooperative clamp loosened, or because H3K36me3 - the PWWP arm's ligand - is itself depleted under treatment, which the same figure reports. There is a third route with independent support: LEDGF chromatin binding is MLL-dependent, since MLL knockdown reduces LEDGF binding at target promoters 3, so anything that reduces MLL occupancy reduces LEDGF occupancy without touching the clamp. Distinguishing these needs the experiment in exp-ledgf-occupancy-menin-inhibitor-monotherapy-panel.
What remains genuinely absent
The counted query (PSIP1 OR LEDGF OR DFS70) AND (revumenib OR ziftomenib OR bleximenib OR enzomenib OR SNDX-5613 OR KO-539 OR JNJ-75276617 OR MI-503 OR MI-3454 OR VTP-50469) returns 0 PubMed records (translation checked; warning list an honest empty set). So:
- No peer-reviewed measurement of LEDGF occupancy under any menin inhibitor exists.
- No measurement at all under ziftomenib or bleximenib; the preprint uses revumenib only.
- No lymphoid measurement: MOLM-13 and MV4-11 are both myeloid, and the disease this project is built around is infant B-ALL.
- No quantification: no fold-change, no dose-response, no time course, and no measurement of the reciprocal question - whether menin occupancy depends on LEDGF.
The ledger line 'nobody has measured LEDGF occupancy under a menin inhibitor' should be rewritten rather than deleted.
| prior graph claim | nobody has measured LEDGF occupancy under revumenib, ziftomenib or bleximenib |
|---|---|
| revised | one 2025 bioRxiv preprint measures it under revumenib (SNDX-5613) in two myeloid human lines; no peer-reviewed measurement exists; none under ziftomenib or bleximenib; none in a lymphoid model |
| direction observed | LEDGF chromatin binding decreased |
| favours | menin primacy (reading A) |
| pubmed count ledgf and named menin inhibitors | 0 |
confounds
[ "study is a menin+LSD1 combination design", "LSD1 inhibition alone produced a comparable reduction", "H3K36me3 also falls, supplying an alternative route", "LEDGF occupancy is MLL-dependent independently of menin" ]
- If LEDGF occupancy already falls under revumenib, a LEDGF-directed agent adds least in exactly the sensitive patients, and its case narrows to the resistant ones where it has never been tested.
- A qualitative occupancy statement in a preprint is the weakest possible foundation for a strategic conclusion, and this entry is deliberately graded moderate for that reason.
- LSD1 inhibition alone reducing LEDGF occupancy means LEDGF occupancy is a non-specific readout of complex health, so using it as a pharmacodynamic biomarker for a menin inhibitor would produce false positives.
- Does LEDGF occupancy fall under menin inhibition in a LYMPHOID KMT2A::AFF1 model? Both measured lines are myeloid and this project's cell-state work found that this disease splits by lineage.
- Is the fall in LEDGF occupancy caused by loss of the cooperative clamp, by loss of H3K36me3, or by loss of MLL occupancy? Three routes, one experiment, and the answer decides whether a LEDGF agent is redundant with or complementary to a menin inhibitor.
- What happens to LEDGF occupancy in a MEN1 gatekeeper-mutant resistant cell under drug? The mutation preserves the menin-KMT2A interaction, so the cooperative enhancement should persist and LEDGF occupancy should NOT fall - a sharp, cheap discriminating prediction.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.preprint
In MOLM-13 and MV4-11 cells profiled by CUT&RUN, the menin inhibitor SNDX-5613 decreased MLL and LEDGF chromatin binding at MLL target loci including FLT3, CDK6, the HOX cluster, MEIS1 and PBX3, while menin occupancy was selectively reduced by menin inhibition and unchanged by LSD1 inhibition.
Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML. · Tayari MM, Dos Santos HG, et al. · bioRxiv 2025What this evidence cannot show
A bioRxiv preprint, not peer reviewed. The LEDGF result is incidental to a menin-plus-LSD1 combination study, is reported qualitatively from metaplots and representative tracks with no fold-change or dose-response, and both cell lines are myeloid. Read in full from Europe PMC fullTextXML for PMC12632788 (31,731 characters, body element present) after the EXT_ID core search returned no pmcid - the pmcid came from the PubMed efetch record instead, which is the reverse of the failure mode the queen brief warns about and worth noting.
Evidence that argues against this (1)
- The same figure reports that the LSD1 inhibitor ORY-1001 alone reduced MLL and LEDGF occupancy to a degree the authors call comparable to menin inhibition, which means loss of LEDGF occupancy is not specific to menin eviction and cannot by itself be attributed to the cooperative clamp. Tayari MM et al. 2025
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The LEDGF IBD binds MLL 1-160 with Kd 14.7 +/- 0.7 uM in the absence of menin and binds the preformed menin-MLL complex with Kd 1.4 uM, an approximately tenfold cooperative enhancement, which is the thermodynamic basis for expecting LEDGF occupancy to fall when menin is evicted.
The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. · Murai MJ, Pollock J, et al. · Blood 2014What this evidence cannot show
In vitro affinities on isolated fragments (NMR for the binary constant, ITC for the ternary). Cooperativity measured on peptides in solution does not translate mechanically into chromatin occupancy, where avidity from the PWWP arm and from nucleosomal DNA also contributes.
Evidence that argues against this (1)
- Nucleosome binding by the PWWP arm is reported to be orders of magnitude tighter than peptide binding and is driven substantially by nucleosomal DNA, so the IBD affinity term may not be rate-limiting for occupancy at all. Koutná E et al. 2023
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
LEDGF chromatin binding is itself MLL-dependent: knockdown of MLL reduced both MLL and LEDGF binding at proximal promoter regions of MLL target genes, so the two associate mutually dependently.
ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia. · Zhu L, Li Q, et al. · Cancer Discov 2016What this evidence cannot show
Murine MLL-AF9-transformed HSPCs, ChIP-qPCR at two loci. Cited here as an alternative causal route for the preprint's observation, not as a claim about menin inhibitors.
Evidence that argues against this (1)
- This is a knockdown of the protein, not a pharmacological eviction from chromatin, and the two need not have the same consequence for a partner's occupancy. Zhu L et al. 2016
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Indirect support that the complex is destabilised as a unit: blocking guanine nucleotide biosynthesis through IMPDH2 reduces LEDGF and menin protein levels, impairs formation and chromatin binding of the MLL-fusion complex, and sensitises MLLr leukaemias to menin inhibition in vivo.
Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition. · Shi X, Li M, et al. · Nat Commun 2025What this evidence cannot show
This lowers LEDGF protein rather than evicting menin, so it speaks to complex interdependence rather than to the cooperativity of the clamp. Read via Europe PMC; open access.
Evidence that argues against this (1)
- An intervention that reduces rRNA transcription and two complex members simultaneously cannot isolate which loss causes the sensitisation, and the authors' own mechanism runs through global translation rather than through the clamp. Shi X et al. 2025
LEDGF chromatin binding falls under SNDX-5613 by CUT&RUN
the tenfold cooperativity predicts this direction
occupancy of this protein under a clinical menin inhibitor
menin occupancy is the cooperative term
- related to →MV4-11 (CVCL_0064) — KMT2A::AFF1, yes, but a ten-year-old's acute monocytic leukaemia with FLT3-ITD
the human KMT2A::AFF1 line in which it was measured
LSD1 inhibition alone reduced LEDGF occupancy comparably
separates the three causal routes behind the observation
the new measurement that weakens the rationale
occupancy is measured in this disease; residence time and nuclear position are not
the LEDGF preprint is dataset 8 of 8 in this census