Oncofusion

start / graph / ana-q118-mef2c-is-lost-in-all-three-human-lines-and-q117s-mouse-retention-does-not-generalise

Analysismoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q118-menin-at-the-human-index-fusion

MEF2C loses occupancy under VTP-50469 in all three human MLL-rearranged lines (MLL1-N 0.18 / 0.25 / 0.04 over floor), which resolves Q117's one locus-level disagreement with the published account in the paper's favour and localises the disagreement to the murine system

also called MEF2C resolved · Q117's Mef2c break does not generalise

Last cycle's mouse re-analysis found one gene, MEF2C, behaving opposite to what the original paper reported. The human data in all three cell lines agrees with the paper, so the odd result was a feature of the mouse experiment rather than a problem with the published account.

The same thing, for a scientist

**Q117 recorded one clean locus-level break with the account this graph holds of PMID 31821784.** The paper's named losers under VTP-50469 include MEF2C; Q117's murine FLAG-MLLAF9 re-analysis gave **Mef2c 0.870 raw, 1.713 over its floor** - retained, and it marked that as a failure to reproduce. **In human cells MEF2C is lost, in every line and by both antibodies** [E1]. Floor-normalised share ratios: | line | MLL1-N | MENIN | DOT1L | |---|---:|---:|---:| | RS4;11 (KMT2A::AFF1) | **0.181** | 0.130 | 0.012 | | MOLM13 (KMT2A::MLLT3) | **0.248** | 0.310 | 0.049 | | ML-2 (KMT2A::AFDN) | **0.040** | 0.025 | 0.000 | All baselines are at the 97-100th percentile of their track, and MEF2C is the only locus in this beat's table represented by **three** TSS windows rather than one, so the figure is a sum over three windows and is the most robust row in the table. **The resolution is that Q117's Mef2c figure is a fact about murine MLL-AF9 in GSE260742 and does not generalise.** Three candidate reasons, none tested here: (i) the mouse line is a retrovirally transformed MLL-AF9 model rather than a patient-derived line; (ii) Q117's Mef2c ratio was read against a Gapdh floor of 0.508 which this beat shows is not a valid floor in either dataset; (iii) the murine measurement is a single 2 kb summit bin while this is a sum over three 6 kb windows. **Reason (ii) is the one worth pursuing**, because it would mean the murine figure needs recomputing against an occupancy-matched floor rather than explaining away: 0.870 raw against a floor of 1.0 rather than 0.508 would give 0.870, still the highest in Q117's table but no longer above 1. **This entry is a correction to a sibling beat's interpretation, not to its measurement**, and it is reported and not edited: Q117's 0.870 is presumably correct as a number.

Facts and figures
scriptanalyses/q118-menin-at-the-human-index-fusion/roseB.py
statusrun
result summaryMEF2C MLL1-N floor-normalised share ratio 0.181 / 0.248 / 0.040 in RS4;11 / MOLM13 / ML-2, against murine FLAG-MLLAF9 at 1.713 over its floor. The human data agrees with the published account and the murine retention does not generalise.
cell lineRS4;11, MOLM13, ML-2
genome buildhg19
shown for fusionKMT2A::AFF1, KMT2A::MLLT3 and KMT2A::AFDN in human lines, all via an MLL1 N-terminus antibody; the murine comparator is FLAG-tagged KMT2A::MLLT3
inputs
[
  "GSE127507 ROSE TSS signal table",
  "Q117 locus-table.json"
]
How this could bite us back
  • MEF2C is the locus where everything this series measures falls together, so it is the natural pharmacodynamic marker of this drug's chromatin action - and a single-locus marker that behaves this cleanly is exactly the kind that gets adopted without the HOXA9 row beside it, where the same drug does something completely different.
Still open
  1. Does Q117's murine Mef2c figure survive recomputation against an occupancy-matched floor rather than the Gapdh floor of 0.508? The binned murine data is described as deleted after use in Q117's own memo, so this needs a re-download rather than a re-read.
  2. MEF2C is lost in all three human lines by all three antibodies, which makes it the most uniformly drug-sensitive locus in this beat. Is that because MEF2C occupancy is the most menin-dependent, or because MEF2C is the locus where all three factors sit in one complex? No co-occupancy measurement addresses it.
Every source behind this entry (1)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    MEF2C floor-normalised within-sample share ratios under 330 nM VTP-50469 are 0.181 (RS4;11), 0.248 (MOLM13) and 0.040 (ML-2) for MLL1-N, 0.130 / 0.310 / 0.025 for MENIN and 0.012 / 0.049 / 0.000 for DOT1L, from baselines at the 97th-100th percentile, summed over the three MEF2C TSS windows the deposited table carries.

    What this evidence cannot show

    NEITHER ANTIBODY IN THIS SERIES IS FUSION-SPECIFIC AND THE ANTIBODY NAME SAYS SO. MLL1n is anti-MLL1 N-terminus (Bethyl A300-086A, lots 5 or 6); the N-terminus is retained in KMT2A::AFF1, so that track is the sum of the fusion and wild-type MLL1 in unknown proportion. MENIN is Bethyl A300-105A Lot 8; menin binds the fusion, wild-type MLL1 and non-KMT2A partners. Q117 could attribute its numbers because its fusion was FLAG-tagged; nothing here can. Every occupancy statement in this beat is about MLL1-N-reactive material or menin-occupied sites, never about the fusion. No scale factor exists for any sample. The depositors state that a Drosophila spike-in was run on one batch, that fly/human ratios were 'found to be small', and that NO spike-in normalisation was applied; no number for that measurement is reported and none is deposited. Every cross-condition figure here is therefore a WITHIN-SAMPLE share or a within-sample rank, which cancel an unknown per-sample scale factor exactly, and never a fold change. n = 1 per antibody per condition per line - there is no replicate anywhere in GSE127507 - so no number here carries a spread and none is precise. The comparison is against Q117's stored murine figure, not against a re-derivation of it, and against what this graph records PMID 31821784 as saying rather than against the paper's figures - Q117 recorded the same limitation for its own locus table and it is inherited here. The ML-2 DOT1L figure of 0.000 has a zero numerator, not a zero denominator; the denominator was asserted non-zero.

    Evidence that argues against this (1)
    • A locus can be lost in three human lines and retained in one murine model without either measurement being wrong - MEF2C dependence differs between MLL-AF9 mouse models and human MLL-r leukaemia, and MEF2C is a documented lineage-specific factor. 'Does not generalise' is the honest verdict and it is weaker than 'Q117 was wrong'. Iqbal Lab oncofusion knowledge graph 2026
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