SCF(Skp2) grips the retained fragment and the fusion escapes it - the clearest documented non-menin contact on that region
also called MLL Skp2 degron · SCF-Skp2 MLL · S-phase degradation of MLL
A disposal machine called SCF-Skp2 normally grabs the front end of KMT2A and destroys it once per cell cycle. Leukaemia fusions keep that front end but are not destroyed, so something about the grip has changed - and that grip is on the exact piece everyone says only menin can hold.
The same thing, for a scientist
MLL is degraded in a biphasic, cell-cycle-timed way: **SCF(Skp2) at S phase, APC(Cdc20) at late M phase**. The reported entry point is the **N-terminal approximately 1400 amino acids** - the fragment KMT2A fusions retain - and **tested prevalent MLL fusions are resistant to degradation**. The Skp2 arm is phosphorylation-gated from the other side: ATR phosphorylation of **S516** disrupts the MLL-SCF(Skp2) interaction. So there is a documented, cell-cycle-regulated, phospho-modulated protein contact on the retained fragment that is not menin and not LEDGF. **What is not documented is the contact's residues, whether it is a classical phosphodegron, and why the fusion escapes it** - the primary paper could not be read past its abstract from this session by any of four routes.
What is established and what is only proposed
Established from the abstract 1: biphasic MLL expression; SCF(Skp2) at S phase and APC(Cdc20) at late M; degradation initiating at the N-terminal ~1400 aa; prevalent MLL fusions resistant; G1/S and M-phase defects when peak expression is abolished; S-phase block on MLL overexpression.
Established from a second paper 2: ATR phosphorylation at S516 disrupts the MLL-SCF(Skp2) interaction, which is what makes this a phosphorylation-gated contact rather than a constitutive one.
Proposed, not established: that impaired degradation is 'the universal mechanism underlying all MLL leukemias'. That is the authors' framing and it competes with the elongation-hijack account this graph runs on.
Unknown: the degron sequence, its residue range, whether Skp2 recognition requires a phosphodegron in the classical F-box sense, which fusions were tested, and whether the fusion's resistance is deletion, masking or altered kinetics.
Why the fusion's resistance is the interesting part
If the fusion retains the degron sequence and still escapes degradation, the escape must come from the 3' partner - masking the degron, changing its accessibility, or changing the kinase input. That is a partner-specific, retained-fragment, non-menin property and it is directly addressable:
- Does Skp2 co-immunoprecipitate with the fusion at all, or only with wild-type MLL?
- Does a menin inhibitor change fusion turnover? The graph already carries the hypothesis
hyp-evicted-fusion-is-degraded-not-displaced, and this is the degradation machinery that hypothesis would have to run through. - Is a molecular glue that restores Skp2 engagement of the fusion feasible? That is a degrader strategy pointed at a contact the fusion has already been shown to evade.
The last question is the one this beat would put in front of the lab, with the caveat in bite_back.
| partner a | SKP2 (SCF E3 ligase substrate receptor) |
|---|---|
| partner b | gene-kmt2a |
| motif b | unmapped; degradation reported to initiate within KMT2A residues 1-1400 |
| fate in fusion | retained (the region), evaded (the degradation) |
| phospho gating | ATR phosphorylation of S516 disrupts the contact |
| tested on fusion | Yes for resistance to degradation ('tested prevalent MLL fusions are resistant'); the identities of the fusions tested are not readable from the abstract |
| readability | primary paper PMID 17908926 abstract-only; four retrieval routes failed 2026-09-19 |
structures
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- A molecular glue restoring SCF(Skp2) engagement would also act on wild-type MLL, whose stabilisation is the proposed mechanism of the CK2-taspase1 route. Restoring degradation and blocking degradation are both on this beat's list of therapeutic ideas, and they cannot both be right in the same patient.
- Skp2 substrates include p27Kip1; anything that redirects SCF(Skp2) activity risks shifting a cell-cycle brake in the wrong direction in normal marrow.
- The primary evidence for the whole contact is one abstract this session could not read past. Acting on it without the full text would be building an intervention on a summary sentence.
- If impaired degradation really is upstream of the leukaemia, then any therapy that stabilises KMT2A protein - including the CK2-taspase1 route - is working against the mechanism it is supposed to exploit.
- Does Skp2 co-immunoprecipitate with KMT2A::AFF1 from a t(4;11) line? The 2007 result says the fusion is not degraded; it does not say the contact is absent, and those are different molecules to drug.
- Where is the degron? Nobody in the accessible literature gives residues. Without them the contact cannot be engineered, mimicked or blocked.
- Is the fusion's resistance conferred by the 3' partner? Comparing KMT2A::AFF1, KMT2A::MLLT3 and KMT2A::ELL turnover in matched cells would say whether this is a shared retained-fragment property or a partner-specific one.
- Does menin-inhibitor-driven eviction of the fusion from chromatin expose it to this ligase? That is the mechanism `hyp-evicted-fusion-is-degraded-not-displaced` would need.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
SCF(Skp2) and APC(Cdc20) mark MLL for degradation at S phase and late M phase respectively, producing a biphasic MLL expression pattern; degradation initiates at MLL's N-terminal approximately 1400 amino acids and tested prevalent MLL fusions are resistant to degradation.
Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. · Liu H, et al. · Genes Dev 2007What this evidence cannot show
KNOWN BUT NOT FULLY READ - abstract only. Four routes failed on 2026-09-19: Europe PMC fullTextXML HTTP 500; efetch db=pmc returned a well-formed record with the publisher note 'The publisher of this article does not allow downloading of the full text in XML form' and no body element; genesdev.cshlp.org HTTP 403; europepmc.org article page HTTP 403. Which fusions were tested, the degron's residues, and whether Skp2 recognition is a classical phosphodegron are therefore NOT established here and must not be inferred from the abstract.
Evidence that argues against this (1)
- The proposal that impaired degradation is the universal mechanism underlying all MLL leukaemias is the authors' own, and a later study of the same regulatory axis reframes it as fine-tuning of Mll1 levels through the Cks1/Cks2 adaptors rather than as the disease's primary lesion, with the therapeutic reading being inhibition of the degradation machinery rather than restoration of it. Grey W et al. 2018
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
ATR phosphorylation of MLL at serine 516 disrupts MLL's interaction with the SCF(Skp2) E3 ligase, making the Skp2 contact phosphorylation-gated.
Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint. · Liu H, et al. · Nature 2010What this evidence cannot show
Abstract read 2026-09-19. The phosphorylation is described in the context of genotoxic stress in S phase, so it is a stress-responsive modulation of the contact rather than the contact's constitutive determinant; nothing in the abstract identifies the residues Skp2 itself recognises.
Evidence that argues against this (1)
- The direction of this switch is the reverse of a classical F-box phosphodegron, in which phosphorylation creates rather than destroys the ligase contact. That difference matters for any degrader design: a molecule that mimicked phospho-S516 would stabilise the substrate, not degrade it. Liu H et al. 2007
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Cks1 and Cks2 interact with both the MllN and MllC subunits of Mll1 and together define Mll1 levels through the cell cycle in concert with SCFSkp2 and APCCdc20; CKS1B and CKS2 are overexpressed in KMT2A-rearranged AML subtypes, and the degradation-pathway inhibitors MLN4924 and C1 reduced proliferation of KMT2A-rearranged lines more than primary controls.
The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability. · Grey W, et al. · Biochim Biophys Acta Mol Cell Res 2018What this evidence cannot show
Abstract read 2026-09-19; full text not retrieved. MLN4924 (pevonedistat) is a NEDD8-activating enzyme inhibitor affecting all cullin-RING ligases, so its selectivity for KMT2A-rearranged lines is not evidence that the Mll1-Cks axis is the mediator. The Cks contact spans both MllN and MllC, which means part of it is lost in the fusion and part retained; the abstract does not resolve which part carries the interaction.
Evidence that argues against this (1)
- This study's therapeutic logic is to inhibit the degradation machinery, i.e. to raise MLL1 levels, while the taspase1 study's logic is also to raise full-length MLL1 levels, and the 2007 study's logic is that failure to degrade MLL is what causes the disease. Three papers on one regulatory circuit disagree about which direction is therapeutic, and none of them tested a fusion-selective intervention. Zhao Z et al. 2019
audits the reagent basis of the Skp2 degron claim: FLAG-tagged fusion in 293T, in vitro degradation
the adaptor that couples MLL1 to SCF(Skp2) and APC(Cdc20)
the partner that interface entry names in free text and had no node for