A menin inhibitor is not a fusion degron, so watching menin leave chromatin under one cannot identify what was holding it there - every model predicts the same result
If you want to know whether the fusion protein is what keeps menin stuck to a gene, you have to remove the fusion and watch menin. A menin-blocking drug does the opposite: it removes menin directly. Menin then leaves whatever was holding it, so the experiment cannot tell you what that was.
The same thing, for a scientist
The two perturbations this project compares are not substitutes. A **degron** destroys the fusion and leaves menin chemically untouched, so residual menin at a fusion-occupied promoter is evidence of a fusion-independent tether - which is the observation behind this project's loose-coupling reading (50.3% menin retention 3 h after the fusion falls to 1.0-2.8%). A **menin inhibitor** occupies the menin pocket that binds the KMT2A MBM motifs, so it disengages menin from **every** KMT2A-family partner at once - the fusion, wild-type MLL1 and MLL2 alike. Under a menin inhibitor, menin leaves fusion promoters under the fusion-tether model *and* under a wild-type-MLL1-tether model *and* under a LEDGF-plus-menin model, because all three routes pass through the pocket the drug occupies. **The experiment has no discriminating power over the tether question by construction**, and a non-reproduction of the degron result under a menin inhibitor is therefore weak evidence about the tether and strong evidence only about the drug.
The truth table, which is the whole content of this entry
| model of what holds menin at a fusion promoter | prediction under a FUSION DEGRON | prediction under a MENIN INHIBITOR |
|---|---|---|
| the fusion, via MBM1/MBM2 | menin leaves | menin leaves |
| wild-type MLL1 at the same promoter, via its own MBM | menin stays | menin leaves |
| LEDGF/PSIP1, with menin as the bridge | menin stays (partly) | menin leaves |
| a menin-independent scaffold | menin stays | menin stays |
Only the degron column separates the rows. Three of the four models are indistinguishable in the menin-inhibitor column, and the fourth - a menin-independent scaffold - is the only one the drug arm could in principle detect, by menin not leaving.
What a menin inhibitor CAN answer that a degron cannot
It is not a worse experiment, it is a different one. A menin inhibitor answers the clinical question - does the drug disengage its target on chromatin in a patient - and a degron cannot, because no patient has a degron. It also answers what happens to the rest of the complex when menin goes while the fusion protein is still being made, which is precisely the state a patient on therapy is in and which no degron models. Both of those are the questions this pair is actually good for.
The corollary this project already holds and should apply here
A DOT1L inhibitor strips menin from fusion-occupied promoters about as effectively as destroying the fusion does (0.467 against 0.437 in the same deposit). So menin displacement is not diagnostic of the menin-KMT2A interface being broken by any route - a third drug with no menin activity produces the same readout. Menin occupancy is a poor reporter of interface engagement, and this entry is the pharmacological half of that same point.
| claim | a menin inhibitor cannot discriminate between models of what tethers menin at fusion promoters, because every tether route passes through the pocket the drug occupies |
|---|---|
| corollary already in this corpus | a DOT1L inhibitor removes menin from fusion promoters about as well as destroying the fusion does (0.467 vs 0.437), so menin displacement is not diagnostic of interface breakage by any route |
| consequence for this beat | the failure of the pre-registered falsifier damages the GENERALITY of the loose-coupling reading and barely touches its MECHANISM |
truth table
{
"fusion_tether": {
"degron": "menin leaves",
"menin_inhibitor": "menin leaves"
},
"wild_type_MLL1_tether": {
"degron": "menin stays",
"menin_inhibitor": "menin leaves"
},
"LEDGF_bridge": {
"degron": "menin stays (partly)",
"menin_inhibitor": "menin leaves"
},
"menin_independent_scaffold": {
"degron": "menin stays",
"menin_inhibitor": "menin stays"
}
}what a menin inhibitor CAN answer
[ "does the drug disengage its target on chromatin in a patient", "what happens to the rest of the complex while the fusion is still expressed" ]
- This concept is a reason not to over-read a negative from a menin-inhibitor occupancy experiment. It is equally a reason not to over-read a positive: menin staying somewhere under the drug would be the interesting result, and nothing here stays.
- Clinically it means occupancy is the wrong pharmacodynamic endpoint for a menin inhibitor. Target-gene expression, which was the endpoint that correlated with remission in the phase 1 trial, is measuring the consequence rather than the engagement, and that is the better choice for the reason this entry gives.
- Is there any perturbation available in primary patient material that removes the fusion without touching menin? A fusion-directed degrader or a breakpoint-specific ASO would be one; neither exists clinically.
- Would a menin inhibitor plus a wild-type-MLL1-selective perturbation separate the wild-type-tether row from the fusion-tether row? That is a two-arm cell-line experiment nobody has run.
- Does menin remain at any promoter class under a menin inhibitor? A menin-independent scaffold is the one model the drug arm could detect, and this beat found nothing above background anywhere - which is weak evidence against it.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Menin inhibitors act by occupying the menin pocket that binds the KMT2A MBM motifs, dissociating menin from KMT2A-family partners generally rather than from the fusion specifically.
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia · Krivtsov AV, Evans K, Gadrey JY, Eschle BK, Hatton C, Uckelmann HJ, Ross KN, Perner F, Olsen SN, Pritchard T, McDermott L, Jones CD, Jing D, Braytee A, Chacon D, Earley E, McKeever BM, Claremon D, Gifford AJ, Lee HJ, Teicher BA, Pimanda JE, Beck D, Perry JA, Smith MA, McGeehan GM, Lock RB, Armstrong SA · Cancer Cell 36:660-673.e11 2019What this evidence cannot show
Established for VTP-50469 in cell lines and mouse models; revumenib (SNDX-5613) is the clinical analogue of the same series and the same binding mode. No structure of revumenib bound to menin is cited here.
Evidence that argues against this (1)
- Soto-Feliciano et al. show that the composition of the MLL complex - specifically the presence of MLL3/MLL4 versus MLL1 - dictates response to menin-MLL inhibition, so the drug's effect is not uniform across KMT2A-family partners and the 'removes menin from everything' simplification is an approximation. Soto-Feliciano YM et al. 2023
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
A fusion degron leaves menin chemically untouched, which is what makes residual menin at fusion promoters interpretable as a fusion-independent tether.
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 82:1140-1155.e11 2022What this evidence cannot show
KMT2A::MLLT3 in HCB1 cord-blood cells; the degron is dTAG-VHL on an HA-FKBP12(F36V) tag, n = 1 per arm, housekeeping-normalised with no spike-in.
Evidence that argues against this (1)
- The degron destroys the fusion over hours, and menin's own off-rate from chromatin is not known, so residual menin at 3 h is also consistent with slow dissociation rather than with a second tether - which is why the 4-day timepoint (0.437, a plateau) carries more of the argument than the 3-hour one. Olsen SN et al. 2022
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Menin is delivered to MLL target genes by LEDGF/PSIP1 with menin as the bridging component, giving a second route to fusion promoters that also passes through menin.
Menin critically links MLL proteins with LEDGF on cancer-associated target genes · Yokoyama A, Cleary ML · Cancer Cell 14:36-46 2008What this evidence cannot show
Biochemistry and ChIP in cell lines; the relative contribution of the LEDGF route in primary infant material is unmeasured, and no LEDGF channel exists in GSE252378.
Evidence that argues against this (1)
- The LEDGF route was established in cell lines with overexpression and co-immunoprecipitation, and its contribution in primary infant material has never been measured; if it is minor in vivo, the truth table's third row carries little weight and the argument rests mainly on the wild-type-MLL1 row. Soto-Feliciano YM et al. 2023
the drug whose mechanism makes the experiment non-discriminating
a menin inhibitor occupies the menin pocket that binds the KMT2A MBM motifs
the LEDGF route is one of the tether models the drug cannot separate
the reason the failed falsifier is weaker evidence than it looks
- related to →KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3)
the degron system the comparison is against
why the drug arm cannot discriminate
menin displacement is not diagnostic of interface engagement