Menin persists on chromatin after the fusion is degraded because LEDGF/PSIP1 supplies a fusion-independent tether - the authors' own proposal, never tested, and the single cheapest experiment that would change how menin displacement is interpreted as a drug readout
also called the LEDGF tether hypothesis · why menin is sluggish · PSIP1 holds menin when the fusion goes
When the cancer fusion protein is destroyed menin stays stuck to DNA, and the likely reason is a second anchor - a protein called LEDGF - that holds menin independently of the fusion. If that is right, a drug that only breaks the menin-fusion contact is attacking the more replaceable of two attachments, which matters both for how well it can work and for how easily cancers escape it.
The same thing, for a scientist
**The statement.** Menin's chromatin residence after acute MLL::AF9 degradation is maintained by **LEDGF/PSIP1**, which binds menin and chromatin independently of the fusion. Removing the fusion removes only one of menin's two anchorages, so menin stays; removing LEDGF as well would clear it. **Where it comes from.** This is **the authors' own explanation**, offered in the discussion of the degron paper and not tested by them: *"In contrast to DOT1L, MENIN is thought to be tethered to chromatin via LEDGF (Yokoyama and Cleary, 2008) independently of MLL::AF9. Additional and/or compensatory anchorage by LEDGF could explain why MENIN dissociates from chromatin more slowly upon MLL::AF9 degradation"* [E1]. The supporting architecture — menin as the physical adaptor linking MLL to LEDGF — is established [E2]. **What makes it worth a hypothesis node rather than a sentence.** It explains three separate observations at once, which is more than a restatement: 1. **Menin retains 80.0% of its peak calls** genome-wide 3 h after fusion degradation while the fusion is at 2.5-7.1% [E3]. 2. **DOT1L leaves before menin**, across three instruments, and DOT1L's tether (AF9) is destroyed with the fusion while menin's second tether is not [E1, E4]. 3. The authors' careful hedge — *"MLL::AF9 contributes to retaining MENIN on chromatin **at certain loci**, suggesting that there are multiple interactions that maintain MENIN occupancy"* [E1] — is exactly what a two-anchor model predicts: fusion-dependence where the second anchor is weak, fusion-independence where it is strong. **Prior probability: 0.45.** The mechanism is plausible, endorsed by the people who ran the experiment, and architecturally supported — but this graph carries an entry asserting `mechanism-ledgf-dispensable-for-fusion-chromatin-retention`, and dispensability for the fusion does not settle the question for menin in either direction. Nothing has been measured.
What would distinguish this from the alternatives
The hypothesis competes with at least three others, and they are separable:
- Residual protein. Some undegraded fusion persists and holds menin. Distinguished by the HA control: at 2.5-7.1% site retention, any residual fusion is at a small minority of sites, so it cannot hold menin at 80%.
- Slow off-rate. Menin simply has a long chromatin residence time and three hours is too short. Distinguished by a later timepoint — and there is none in this or any deposit, which is why
absence-q139-no-menin-chip-exists-beyond-three-hours-under-any-degronmatters. - Wild-type MLL1. Menin is held by endogenous wild-type KMT2A, which the degron does not touch. This is the most serious competitor, it is not exclusive with the LEDGF model, and it is the reason the experiment below has a KMT2A arm.
If menin is held by wild-type MLL1 rather than by LEDGF, the therapeutic reading inverts: a menin inhibitor would then be displacing menin from normal-cell complexes at least as much as from the oncogenic one.
| statement | LEDGF/PSIP1 supplies a fusion-independent chromatin tether for menin, so degrading MLL::AF9 removes only one of menin's two anchorages and menin persists; removing LEDGF as well would clear menin from chromatin. |
|---|---|
| origin | literature-gap |
| prior probability | 0.45 |
predictions
[ "MEN1 ChIP 3 h after fusion degradation in PSIP1-depleted HCB1 shows substantially lower menin retention than in PSIP1-intact HCB1, at the fusion's own sites and genome-wide.", "PSIP1 ChIP itself is largely unchanged by fusion degradation at 3 h - the tether does not depend on the fusion.", "Menin sites that are LEDGF-co-occupied retain menin after fusion degradation; menin sites without LEDGF do not. This is testable from existing public LEDGF ChIP in a KMT2A-rearranged line without generating any new degron data.", "A menin inhibitor and fusion degradation should converge on menin displacement in PSIP1-depleted cells and diverge in PSIP1-intact cells." ]
experiments
[ "exp-q139-menin-chip-after-fusion-degradation-with-a-psip1-arm-and-a-spike-in" ]
analyses
[ "ana-q139-menin-peak-calls-persist-genome-wide-three-hours-after-the-fusion-is-degraded" ]
falsifiers
[ "In HCB1 or any MLL-AF9-FKBP12 line, if MEN1 ChIP 3 h after dTAG-VHL 500 nM shows top-decile summit retention within 10 percentage points of the PSIP1-intact value (i.e. no better than 70% vs 80%) after PSIP1 knockdown verified to below 20% of protein, the LEDGF tether is not what holds menin and this hypothesis is refuted.", "If publicly available LEDGF ChIP in a KMT2A-rearranged human line shows that menin peaks retained after fusion degradation are NOT enriched for LEDGF co-occupancy relative to menin peaks lost - odds ratio below 1.5 - the hypothesis loses its cheapest support without any new experiment.", "If a MEN1 ChIP at 24 h or later after degradation shows menin retention collapsing to HA-like levels, then menin's persistence at 3 h is a slow off-rate rather than a second anchorage, and the hypothesis is superseded rather than refuted.", "If menin retention after fusion degradation is abolished by depleting endogenous wild-type KMT2A rather than PSIP1, the anchor is wild-type MLL1 and not LEDGF." ]
- If menin has a second, fusion-independent anchorage, then a menin inhibitor is attacking the more buffered of two contacts and a resistance mechanism exists that requires no MEN1 mutation at all - simply stronger LEDGF engagement.
- It also predicts that menin displacement measured in a patient sample is a poor readout of whether the oncoprotein has been disabled, because the fraction of menin that moves is the fraction not held by the second anchor.
- Conversely, if the hypothesis is right it argues for the LEDGF-IBD interface as a combination target - but this graph already records that no LEDGF agent has ever been tested in menin-inhibitor-resistant disease, so that is a gap, not an option.
- Is there any public LEDGF/PSIP1 ChIP in a KMT2A-rearranged human line that could be intersected with the menin peaks retained here? That would test the central prediction at the cost of a download, and it has not been searched for.
- Does the two-anchor model predict which loci are the authors' 'certain loci' where the fusion does contribute to menin retention? If retained and lost menin sites differ systematically in LEDGF occupancy, the model earns its keep; if they do not, it is a just-so story.
- Menin is an adaptor between MLL and LEDGF in the Yokoyama-Cleary architecture. If the tether requires an MLL protein in the middle, what plays that role once the fusion is gone - endogenous wild-type KMT2A, another KMT2 family member, or nothing?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The authors propose LEDGF as a compensatory, fusion-independent anchorage explaining why menin dissociates more slowly than DOT1L after MLL::AF9 degradation, and conclude that multiple interactions maintain menin occupancy.
MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape. · Olsen SN, Godfrey L, Healy JP, Choi YA, Kai Y, Hatton C, Perner F, Haarer EL, Nabet B, Yuan GC, Armstrong SA · Molecular Cell 2022What this evidence cannot show
This is a DISCUSSION-SECTION PROPOSAL, phrased as 'could explain'. The authors performed no LEDGF experiment in this paper - there is no PSIP1 ChIP, knockdown or degron arm anywhere in GSE173599. Treating it as a finding rather than as the authors' hypothesis would be a misreading, and the confidence here reflects that.
Evidence that argues against this (1)
- This graph carries mechanism-ledgf-dispensable-for-fusion-chromatin-retention. If LEDGF is dispensable for retaining the fusion on chromatin, the assumption that it is a dominant chromatin tether in this system is weakened, and the two entries should be adjudicated before either is relied on. Oncofusion knowledge graph 2026
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Menin serves as a molecular adaptor physically linking MLL to LEDGF on chromatin, and LEDGF is required for MLL-dependent transcription and leukemic transformation.
Menin critically links MLL proteins with LEDGF on cancer-associated target genes. · Yokoyama A, Cleary ML · Cancer Cell 2008What this evidence cannot show
Abstract-level reading. The architecture is established in HeLa, U937 and mouse myeloid progenitors, 14 years before the degron experiment and in systems without one. It shows the menin-LEDGF-MLL link exists; it does not show that the link persists, or that it bears load, once the fusion is removed. That step is precisely what this hypothesis asserts and what no experiment has tested.
Evidence that argues against this (1)
- In the Yokoyama-Cleary architecture, LEDGF is recruited THROUGH menin's interaction with MLL - menin is the adaptor between them. If LEDGF's chromatin engagement with menin requires an MLL protein in the middle, then degrading the fusion should weaken the LEDGF tether too, and the hypothesis would need endogenous wild-type KMT2A to supply that middle term. Yokoyama A et al. 2008
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
Menin retains 80.0% of its strongest peak calls genome-wide 3 h after fusion degradation, in cells where the fusion's own tag retains 2.5-7.1%.
GSE173599, samples GSM5271682 / GSM5271684 (HCB1 MEN1 ChIP, DMSO and dTAG-VHL 500 nM, 3 h) · Olsen SN, Armstrong SA, et al. · NCBI Gene Expression Omnibus 2022What this evidence cannot show
n = 1 per arm, no replicate, no spike-in, no noise floor. Genome-wide peak presence, which the authors' own target-restricted signal measure shows is the wrong instrument for the locus-level question. HCB1 is KMT2A::MLLT3, not the index fusion.
Evidence that argues against this (1)
- The same paper reports more than 50% of menin signal lost at MLL::AF9 target genes at the same 3 h timepoint. If menin is substantially displaced where the fusion actually was, the amount of persistence a LEDGF tether needs to explain is smaller than the genome-wide figure suggests. Olsen SN et al. 2022
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
DOT1 binds AF9 directly and DOT1L has three AF9 binding sites whose graded disruption grades H3K79 methylation, so the DOT1L tether is destroyed along with the fusion while menin's putative second tether is not.
Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. · Biswas D, Milne TA, Basrur V, Kim J, Elenitoba-Johnson KS, Allis CD, Roeder RG · Proceedings of the National Academy of Sciences USA 2011What this evidence cannot show
Abstract-level reading, paired in the citing paper with Kuntimaddi et al. 2015 (PMID 25921540). Biochemical reconstitution and structural work, not kinetics after acute protein removal. The asymmetry between a direct AF9-DOT1L tether and a redundant menin tether is an inference from architecture, not a measured comparison of residence times.
Evidence that argues against this (1)
- 68.7% of DOT1L peak calls survive fusion degradation genome-wide, so most DOT1L chromatin residence is also fusion-independent. The direct-tether asymmetry is a statement about the fusion-dependent fraction, not about where each protein mostly sits. NCBI Gene Expression Omnibus 2022
The observation the hypothesis exists to explain: menin at 80.0% retention while the fusion is at 2.5-7.1% in the same cells and the same three hours.
PSIP1/LEDGF is the proposed fusion-independent anchorage. The hypothesis stands or falls on whether depleting PSIP1 converts menin from persistent to displaced after fusion degradation - an experiment nobody has run.
The decisive experiment, and it is four additions to a protocol that already exists: a PSIP1 arm, a spike-in, replicates, and timepoints past three hours.
UNRESOLVED TENSION, FLAGGED NOT SUPPRESSED: if LEDGF is dispensable for retaining the FUSION on chromatin, that does not settle whether it retains MENIN once the fusion is gone - but the two entries pull in opposite directions and should be adjudicated before either is relied on.
The two-anchor model predicts the ordering: DOT1L's single direct AF9 tether is destroyed with the fusion, menin's second tether is not, so DOT1L leaves first.
quantifies that hypothesis's central unknown: the fusion-independent pool is about half of menin at those promoters