A tempting second finding that does NOT survive its control: about half of each treated sample's peaks are absent from DMSO, but the two independent VTP-50469 libraries share only 10.5% of their gained sites - against 7.7%, 8.1% and 10.6% for the DOT1L-inhibitor arms - so the gained peaks are threshold noise and there is no evidence of redistribution
also called GSE149183 gained-peak null
After treatment, roughly half the spots the experiment picked up were new ones. It would be exciting if the protein had moved somewhere specific - but the two independent experiments on the same drug barely agree about where the new spots are, which means they are just measurement noise.
The same thing, for a scientist
**The tempting reading.** Every treated sample calls a large fraction of peaks absent from its DMSO reference: MEN1 VTP-50469 49.7% novel (547/1,101), MEN1 EPZ5676 54.2%, MEN1 compound 10 58.0%, MEN1 compound 11 44.5%, DOT1L VTP-50469 66.1% [E1]. MEN1 VTP-50469's strongest peak reaches **88.19-fold, the highest in the whole deposit**, above DMSO's 58.49. That looks like menin being redirected somewhere, and 'where does the displaced share go' is a live question in this corpus. **The control that kills it.** If VTP-50469 relocates the menin/DOT1L module to a specific set of sites, the **two independently immunoprecipitated VTP libraries should gain the same sites**. Restricting to peaks absent from BOTH DMSO peak sets, MEN1 VTP-50469 has 380 such peaks and DOT1L VTP-50469 has 922; **40 of the 380 overlap, 10.5%** [E1]. The null is the same quantity computed for arms that should NOT share a VTP-specific relocation - the MEN1 DOT1L-inhibitor arms against the same DOT1L-VTP gained set: | MEN1 arm, gained peaks | n | hitting the DOT1L-VTP gained set | fraction | |---|---:|---:|---:| | **VTP-50469** | 380 | 40 | **10.5%** | | EPZ5676 | 702 | 54 | 7.7% | | compound 10 | 827 | 67 | 8.1% | | compound 11 | 433 | 46 | **10.6%** | **Compound 11 matches the DOT1L-VTP gained set slightly better than VTP-50469 does.** There is no VTP-specific gained-site programme. The gained peaks are what a q < 0.01 threshold does to broad, near-threshold signal when the library composition shifts [E1]. **Why this is written down rather than left out.** It is the second-most interesting thing this deposit appeared to contain, it is the kind of result that travels well, and it is false. The corpus already holds `where-does-the-displaced-fusion-share-go` as an open question; **this deposit does not answer it and specifically cannot be cited as evidence that it does.**
What this does NOT weaken
The headline result is a statement about losses at pre-specified loci, not about gains. The gained peaks being noise does not touch the 0/19, and in one respect it strengthens the read on the VTP library being alive: a sample that calls 1,101 peaks, 67 of them above 5-fold, with its strongest at 88.19, is producing signal - the signal is just not at the fusion's target genes and not anywhere reproducible either.
| script | analyses/menin-inhibitor-against-dot1l-inhibitors-in-one-deposit/run.py |
|---|---|
| status | run |
| geo | GSE149183 |
| verdict | no VTP-specific gained-site programme; gained peaks are threshold noise |
| max fold enrichment men1 vtp | 88.19 |
| max fold enrichment men1 dmso | 58.49 |
| rows dropped by any filter | 0 |
novel peak fraction — the numbers behind the chart
{
"MEN1_VTP50469": 0.497,
"MEN1_EPZ5676": 0.542,
"MEN1_comp10": 0.58,
"MEN1_comp11": 0.445,
"DOT1L_VTP50469": 0.661,
"DOT1L_EPZ5676": 0.516,
"DOT1L_comp10": 0.562,
"DOT1L_comp11": 0.617
}gained site concordance with DOT1L VTP gained set — the numbers behind the chart
{
"MEN1_VTP50469": 0.1053,
"MEN1_EPZ5676": 0.0769,
"MEN1_comp10": 0.081,
"MEN1_comp11": 0.1062
}- Reporting drug-induced 'gained' binding sites from single-replicate ChIP-seq is a standard way to generate a resistance or compensation story that does not replicate. Any compensation mechanism proposed from gained peaks in this deposit would be built on noise.
- Where DOES displaced menin go, if anywhere? Answering it needs within-condition replicates so that a reproducible gained set can be separated from threshold noise - a two-replicate MEN1 ChIP under VTP-50469 would settle it and no deposit in this corpus has one.
- Is the 88.19-fold MEN1 peak in the VTP-50469 sample reproducible or a single-library artefact? It is the strongest peak in the deposit and it appears in the arm where menin is supposedly evicted, which makes it either the most interesting site in the experiment or a blacklist region. Its coordinates are in results.json and were not annotated.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
Re-analysis of the ten deposited peak tables: novel-peak fractions run 44.5-66.1% across the eight treated samples; restricted to peaks absent from both DMSO peak sets, MEN1 VTP-50469 (n=380) shares 10.5% with DOT1L VTP-50469 (n=922), against 7.7% (EPZ5676), 8.1% (compound 10) and 10.6% (compound 11) for the control arms.
analyses/menin-inhibitor-against-dot1l-inhibitors-in-one-deposit (PREREGISTRATION.md, run.py, results.json) - this repository, re-analysis of the ten deposited GSE149183 MACS2 peak tables · Oncofusion knowledge graph 2026What this evidence cannot show
The control arms are not a formal permutation null - they are three empirical comparators, and with one VTP pair there is no way to build a distribution. The claim is only that the VTP value sits inside the range of the comparators, which it does, at the bottom of it in one case.
Evidence that argues against this (1)
- A real relocation could be invisible here if the MEN1 and DOT1L modules relocate to DIFFERENT places - the test assumes they move together, which is what a complex-eviction model predicts but is not guaranteed. A within-factor replicate would be the right control and this deposit has none. Oncofusion knowledge graph 2026
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
The deposited peak calls are broad and near-threshold, with median fold-enrichment 2.79-3.40 in all ten samples and MACS fragment-size estimates of 822-1112 bp, which is the regime in which threshold crossing generates large apparent gained-peak sets.
NCBI GEO GSE149183 - MEN1, DOT1L and H3K79me2 ChIP-seq in MOLM13 and RS4;11 under DMSO, VTP-50469, EPZ5676, compound 10 and compound 11; 31 samples, Homo sapiens; SubSeries of GSE149185, BioProject PRJNA627612, SRA SRP258055 · NCBI Gene Expression Omnibus 2020What this evidence cannot show
This is a description of the deposited files rather than a test of the mechanism by which gained peaks arise.
Evidence that argues against this (1)
the gained peaks are noise, so nothing in this deposit undercuts the loss result by reinterpreting it as relocation
no VTP-50469-specific gained-site programme: 10.5% concordance against controls of 7.7-10.6%