Four days after the fusion is destroyed, menin signal at non-fusion promoters is 27% higher than control
Destroying the fusion for four days does not just remove menin from the fusion's genes - menin shows up more strongly at other genes. It looks like menin is relocating rather than being cleared, although the way the data were scaled makes that hard to prove.
The same thing, for a scientist
At 4 days of dTAG-VHL, median MENIN TSS signal is **0.437** at the authors' target genes (n=202) and **1.271** at the bottom half of HA occupancy (n=2,283) - a 27% **increase** at non-fusion promoters. No other arm in the same table does this (EPZ-5676 0.744, VTP-50469 0.651 at the same genes). **Read this cautiously.** The arms are housekeeping-normalised with no spike-in, which forces the global signal to a constant; if a large pool of menin leaves a small number of very strong fusion promoters, the normalisation must push everything else up. So the observation is consistent with genuine redistribution **and** with a normalisation artefact, and the deposit cannot distinguish them. What it does establish is that menin is not being degraded or globally cleared - its measured distribution shifts away from fusion promoters and toward everything else.
Why it cannot be resolved here, stated as a limit not a hedge
Distinguishing redistribution from renormalisation requires an external scale: a spike-in chromatin control, or a quantitative western of chromatin-bound menin. Neither exists in GSE173599. Under a housekeeping normalisation, a rise somewhere is the arithmetic consequence of a fall elsewhere. Trust the shape of a share; distrust its level.
This corpus has already shown that a share manufactures exactly this shape
ana-a-share-renders-a-global-collapse-as-a-rising-gradient-into-the-bulk demonstrated, against a spike-in ground truth in GSE149183, that a within-sample share reports a genuine global collapse as signal moving out of the busy regions and into the quiet ones by up to ten-fold, when nothing moved. The 1.271 reported here is that shape. The prior probability that this observation is an artefact should therefore be read as high, and this entry is filed at weak confidence for that reason rather than on general caution.
Why it is worth recording anyway
If menin does redistribute, it has a chromatin address independent of the fusion - which is the published model, in which LEDGF/PSIP1 delivers the menin-MLL1 module to chromatin 3 - and a menin inhibitor is then not simply removing menin from the genome but changing where it sits, including at wild-type MLL1 targets. That is a different toxicity profile from clearance.
Scale and limits
No spike-in exists anywhere in GSE173599, so every number is a within-sample share, and the treated arms are scaled by a 21-gene housekeeping panel whose own raw 3 h H3K27ac ratio averages 0.809 and is forced to 1. A housekeeping normalisation DEFINES the global change to be zero, so only the DIFFERENCE between strata is measurable; a uniform genome-wide loss of any of these proteins would be invisible here. n = 1 per arm for every channel except HA, which has two independent 3 h batches. The cells are HCB1, transformed by KMT2A::MLLT3 (MLL::AF9) - NOT the index fusion of this project, KMT2A::AFF1 - and a prior beat in this corpus found that per-gene ordering transfers between MLLT3 and AFF1 lines while magnitude does not.
| script | analyses/menin-retention-by-ha-occupancy/analyze_controls.py |
|---|---|
| status | run |
| result summary | MENIN 4 d dTAG-VHL: 0.437 at target genes, 1.271 at non-occupied genes. At 3 h the non-occupied stratum is 0.974. The rise cannot be separated from the housekeeping normalisation. |
| peak width ratio note | Signal instrument. The MEN1 3 h peak arm has a width ratio of 0.93; no MEN1 peak file exists for the 4-day dTAG arm in the downloaded set. |
inputs
[ "GSE173599_TSS_signal_Figure4.xlsx", "GSE173599_TSS_gene_body_signal_Figure3.xlsx" ]
- If a fusion-directed therapy relocates menin rather than clearing it, the menin that arrives elsewhere is acting on wild-type MLL1 targets, which is a plausible route to on-target normal-tissue effects that an occupancy-clearance model would not predict.
- A spike-in-normalised MENIN ChIP at 3 h and 4 d would settle redistribution versus renormalisation in a single experiment and is the cheapest unresolved question this deposit raises.
- If menin redistributes, does it go to wild-type MLL1 targets, to LEDGF sites, or to neither?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
At 4 days of dTAG-VHL, median MENIN TSS signal is 0.437 at MLL::AF9 target genes and 1.271 at non-occupied genes.
GSE173599_TSS_signal_Figure4.xlsx - per-gene HA, DOT1L and MENIN TSS signal after 4 days of EPZ-5676, VTP-50469 or dTAG-VHL (batch 1912x2) · Olsen SN et al. · NCBI GEO supplementary file 2022What this evidence cannot show
Housekeeping-normalised with no spike-in, so a rise at non-target genes is not separable from the normalisation. n=1 per arm; 4-day treatment with a differentiation confound.
Evidence that argues against this (1)
- The same normalisation means the measurement cannot exclude that total chromatin-bound menin fell and the non-target rise is entirely arithmetic. Olsen SN et al. 2022
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
At 3 h in the same system the non-occupied stratum sits at 0.974, i.e. flat, so the 4-day rise is not present at the early timepoint.
GSE173599_TSS_gene_body_signal_Figure3.xlsx - per-gene housekeeping-normalised TSS and gene-body ChIP signal, DMSO vs dTAG-VHL 3 h and 24 h, 16 channels · Olsen SN et al. · NCBI GEO supplementary file 2022What this evidence cannot show
Different sequencing batch and a different sheet; the two timepoints are not depth-matched.
Evidence that argues against this (1)
- The 3 h and 4 d arms are different sequencing batches with different floors, so the absence of a rise at 3 h could be a batch property rather than a kinetic one. Olsen SN et al. 2022
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin physically links MLL proteins to chromatin through LEDGF/PSIP1, supplying a fusion-independent chromatin address for the menin-MLL1 module.
Menin critically links MLL proteins with LEDGF on cancer-associated target genes · Yokoyama A, Cleary ML · Cancer Cell 14(1):36-46 2008What this evidence cannot show
Biochemistry and transformation assays in mouse myeloid progenitors and human cell lines; not a genome-wide occupancy measurement after fusion loss.
Evidence that argues against this (1)
- A LEDGF-based address predicts menin should already be at those promoters before the fusion is removed, in which case there is nothing to redistribute and the 1.271 must be normalisation. Yokoyama A et al. 2008
menin signal at non-fusion promoters is 27% above control 4 d after fusion degradation - redistribution or renormalisation, indistinguishable here
LEDGF/PSIP1 supplies the fusion-independent chromatin address that a redistribution reading would require
- ← related toA housekeeping normalisation defines the global change to be zero, so only redistribution is measurable
the 27% rise at non-fusion promoters is exactly what renormalising a large concentrated loss produces
the 1.271 rise at non-fusion promoters is the artefact shape that entry demonstrated, which is why this observation is filed weak