Kerry 2017's 'sufficient but not necessary' is a figure title with no experiment behind the second half - and the paper's own knockdowns run the other way
also called Kerry Figure 2 title · menin sufficiency and necessity for fusion recruitment · the tethering experiment
A well-known claim says the fusion protein does not really need menin to find its place on DNA. We went to the source and read it: that claim appears only in the title of one figure. The experiments in that figure show the opposite - when menin is knocked down, the fusion binds less.
The same thing, for a scientist
This beat was dispatched on the premise that Kerry et al. 2017 show the menin interaction is *sufficient but not necessary* for fusion recruitment, and that a menin inhibitor might therefore relocate rather than remove the fusion. **The premise is half right and the half that is wrong is the load-bearing half.** Read in full text (PMC5263239): the phrase appears **once, as the title of Figure 2**, *The MLL-AF4:Menin Interaction Is Sufficient but Not Necessary for Recruitment*. The results-section heading two paragraphs earlier reads *The Menin:MLL-AF4 Interaction Is **Sufficient** for Recruitment* - without the second clause [E1]. The word *necessary* occurs three times in the whole paper, and not one occurrence is about menin: one is about PAFc, one about spreading targets, one in the funding disclaimer [E1]. **The sufficiency half has a real experiment**: a TetR/TetO array inserted into a BAC lacking promoter, enhancer or uCpG features and integrated into chromosome 8 of mouse ES cells; TetR-MLL-AF4 recruits menin but not PAF1, doxycycline abolishes it, and the reciprocal TetR-menin line recruits transfected MLL-AF4 [E1]. **The necessity half has no experiment in that paper that supports it, and the experiments it does have point the other way**: siRNA knockdown of menin in SEM cells **reduces MLL-AF4 binding** at gene targets, and the discussion's summary sentence is that *MLL-AF4 and Menin co-stabilize each other's binding to gene targets* [E1]. The strongest reading available for 'not necessary' is that the siRNA knockdowns reduce rather than abolish fusion binding - but an incomplete knockdown cannot distinguish *not necessary* from *not fully depleted*, and the paper reports no depletion-versus-residual-occupancy curve. **Note also that the coordinator's cycle-45 log carried the same premise** (*Kerry's tethering experiment says the menin interaction is SUFFICIENT but NOT NECESSARY*). The tethering experiment says sufficient. The rest of the paper says co-stabilisation.
Sentence-level audit of the source
| location in PMID 28076791 | text | supports |
|---|---|---|
| Results heading | The Menin:MLL-AF4 Interaction Is Sufficient for Recruitment | sufficiency |
| Figure 2 title | The MLL-AF4:Menin Interaction Is Sufficient but Not Necessary for Recruitment | the only occurrence of the necessity claim |
| Fig 2B, S2A-C | TetR-MLL-AF4 recruits menin, not PAF1; TetR-menin recruits MLL-AF4; TetR-PAF1 does not | sufficiency, both directions |
| Fig 2E-H column ii | menin siRNA reduces MLL-AF4 and PAF1 binding at target genes | necessity, not its absence |
| Discussion, first sentence | MLL-AF4 and Menin co-stabilize each other's binding to gene targets | mutual dependence |
| Intro (citation, not data) | a minimal CXXC domain can be recruited to the HoxA9 locus in the absence of a Menin/LEDGF interaction (Milne 2010) | the likely origin of the necessity clause - and it is about a minimal CXXC construct, not the fusion |
The figure title is a fair shorthand for menin tethering is enough to place the fusion, and the fusion can also be placed by other means - a reasonable authorial summary of the field. It is not a result of this paper, and it should not be cited as one.
Why this matters for the relocation question, and why the question survives anyway
If menin were genuinely unnecessary for fusion placement, relocation under a menin inhibitor would be the natural expectation - the CXXC domain would simply sample the rest of the uCpG landscape. The sufficiency-only reading makes relocation a weaker prior, because the same paper's knockdowns say fusion occupancy falls when menin goes.
But the relocation question does not depend on the necessity claim. It rests on two facts that survive intact: the fusion occupies only 20% of unmethylated CpG sites while CFP1 sits on 50% and KDM2B on 89% (ana-the-fusion-sits-on-one-fifth-of-the-unmethylated-cpg-sites-and-menin-picks-which) 2, and the fusion is not globally displaced by a menin inhibitor (mechanism-vtp-50469-does-not-globally-displace-the-fusion-from-chromatin) 3. A protein that stays on chromatin while its principal selectivity factor is removed is precisely the case in which redistribution is worth testing - and it is more worth testing under retention than under eviction, because there is something left to redistribute.
| script | none - full-text reading of PMC5263239 on 2026-09-21 |
|---|---|
| status | run |
| result summary | 'Sufficient but not necessary' occurs once, as a figure title. No experiment in the paper tests necessity; the menin siRNA arm reduces fusion binding and the discussion concludes co-stabilisation. The brief's premise and the cycle-45 king log both need correcting. |
| occurrences of necessary | 3 |
| occurrences about menin | 0 |
| shown for fusion | KMT2A::AFF1 in SEM for the knockdowns and the 20% figure; a TetR-MLL-AF4 construct in mouse ES cells for the tethering |
inputs
[ "Europe PMC fullTextXML for PMC5263239" ]
- If the menin contact really is necessary as well as sufficient in the index fusion, the interface hypothesis is stronger than this graph has been claiming - but the same fact removes the comforting explanation for why menin inhibitors do not clear the fusion from chromatin, and leaves retention needing a different mechanism (CXXC, LEDGF, SEC, or simple slow off-rate).
- Beats and briefs in this project have now twice propagated a claim from a figure title or an abstract sentence rather than a result. Any intervention argument built on 'menin is dispensable for fusion placement' should be re-derived before it reaches a grant or a protocol.
- Has anyone ever run the experiment the figure title implies - complete, acute menin removal (degron, not siRNA) with genome-wide fusion occupancy read out? A degron on MEN1 plus a tagged endogenous fusion would answer sufficiency and necessity in one experiment, and would be the cleanest test of the menin-interface hypothesis anyone has proposed.
- Is the residual MLL-AF4 binding after menin knockdown proportional to residual menin, or does it plateau? A plateau would be real evidence of a menin-independent tether; proportionality would close the question.
- How many entries in this graph cite Kerry 2017 for a necessity or sufficiency claim rather than for the spreading result? The paper is cited 35 times here and its most-quoted sentence may be its figure title.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In the full text of Kerry et al. 2017 the phrase 'sufficient but not necessary' appears only as the title of Figure 2; the corresponding results heading says only 'sufficient'; the word 'necessary' occurs three times, none of them about menin; the TetR/TetO experiments demonstrate sufficiency in both directions; siRNA knockdown of menin reduces MLL-AF4 binding at target genes in SEM cells; and the discussion concludes that MLL-AF4 and menin co-stabilize each other's binding.
MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia. · Kerry J, Godfrey L, Repapi E, et al. · Cell Rep 2017What this evidence cannot show
This is a reading of one paper's text and figures, performed on the Europe PMC full-text XML of PMC5263239 on 2026-09-21; figure images were not inspected, so a panel within Figure 2 could in principle show a necessity test not described in the legend or body, and the legend enumerates panels A-H with no such panel. Supplementary Figures S2A-S2G were read only through their in-text descriptions. The siRNA knockdown is a ChIP-qPCR at selected loci, not genome-wide, with at least three biological replicates and no reported knockdown efficiency for menin at the protein level in the text.
Evidence that argues against this (2)
- A defensible alternative reading is that 'not necessary' refers to the residual MLL-AF4 binding that persists after menin siRNA, i.e. the authors are describing incomplete loss. If so, the claim is real but very weak: incomplete siRNA depletion cannot separate 'not necessary' from 'not depleted', and this paper reports no depletion-versus-occupancy dose relationship. Kerry J et al. 2017
- There is independent support for menin-independent placement of a CXXC module: a minimal CXXC domain has been reported recruited to the HoxA9 locus without a menin or LEDGF interaction, and Kerry cite it in their introduction. That is a construct, not the fusion, and Kerry's own data in SEM go the other way, so it cannot be used to license 'the fusion does not need menin'. Kerry J et al. 2017
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In SEM cells (human infant-derived t(4;11) KMT2A::AFF1), MLL-AF4 binding occurred at only 20% of unmethylated CpG sites, while CFP1 and KDM2B bound 50% and 89% respectively, and MLL(N) signal correlated with menin at r-squared 0.96 at fusion peaks against 0.27 for menin versus CFP1.
MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia. · Kerry J, Godfrey L, Repapi E, et al. · Cell Rep 2017What this evidence cannot show
Peak-overlap percentages from Venn analysis, sensitive to peak-calling stringency, as the authors themselves note for the small set of MLL-AF4 sites not overlapping uCpG. One cell line, one fusion. The correlation is between ChIP signals from two different antibodies with different efficiencies, so r-squared 0.96 describes co-variation of signal, not stoichiometry.
Evidence that argues against this (1)
- High MLL(N)-menin correlation at MLL-AF4 peaks is partly guaranteed by the peak set being defined from MLL(N) ChIP in the first place, and by menin and the fusion being in one complex. It supports menin marking the used subset; it does not by itself show menin chooses it. Krivtsov AV et al. 2019
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
A menin inhibitor does not globally displace MLL1 or, in a line where all MLL1n signal is fusion, the fusion itself from chromatin; losses are restricted to a small named set of loci.
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. · Krivtsov AV, Evans K, Gadrey JY, et al. · Cancer Cell 2019What this evidence cannot show
See mechanism-vtp-50469-does-not-globally-displace-the-fusion-from-chromatin for the full caveat set: TSS-anchored quantification, one timepoint, adult-derived lines, no residual-fraction statistic.
Evidence that argues against this (1)
- The murine MLL-AF9 arm of a different study reports a significant decrease in MLL1 chromatin enrichment under MI-503, so retention is not uniform across systems. Soto-Feliciano YM et al. 2023
corrects what Kerry 2017 establishes about menin's role in fusion recruitment
the sufficiency and necessity claims concern this fusion in SEM
same paper, same full-text reading; that entry's figures are reconfirmed here
strengthens the interface hypothesis: menin is co-required, not merely sufficient
removes the premise the relocation hypothesis was originally built on, lowering its prior
- related to →Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so
the address is not contested and it is also not freely available to the fusion without menin