ENL stays after the fusion leaves — an epigenetic lesion that outlives the protein that made it

One. This entry rests on one primary patient sample, profiled as part of a 36-sample oncoprotein-occupancy survey, and it says so throughout. The observation is that in the sample that lineage switched during revumenib treatment, the oncoprotein and menin were reduced to undetectable levels but ENL persisted on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program 1.

The reason a single observation earns an entry is the logical structure of what it shows. Every other resistance mechanism in this beat is compatible with the idea that the drug did not fully work: the drug could not bind (MEN1 mutation), a parallel input substituted (RAS), the output was re-created from other loci (PRC1.1), or a downstream step failed (TP53). Here the drug worked completely by its own definition — menin gone, fusion gone — and the target loci were still occupied and still active. No amount of better pharmacology addresses that.

ENL is a YEATS-domain reader of acylated histones and a component of the super elongation complex; it is a physiological partner of the KMT2A complex and also one of the recurrent KMT2A fusion partners in its own right (KMT2A::MLLT1). The graph already carries gene-mllt1 as both a canonical fusion partner and an interactome member.

That dual role is the point. A cofactor that is recruited by the oncoprotein but which then reads a histone mark rather than binding the oncoprotein has no reason to leave when the oncoprotein does. The oncoprotein writes the state; the reader maintains it. This is the definition of an epigenetic lesion in the strict sense — a heritable chromatin configuration that no longer requires the initiating signal — and it is exactly the configuration for which a protein-protein interface inhibitor is the wrong tool.

hyp-apparent-authority-residual-fusion-occupancy (in analogy/) predicts: at saturating menin-inhibitor concentration a reproducible subset of KMT2A::AFF1 chromatin binding sites retains fusion occupancy through menin-independent tethering (CXXC-DNA, LEDGF/PSIP1 PWWP, AFF1-SEC contacts). Its first listed falsifier is: CUT&RUN under saturating drug shows essentially complete, uniform loss of fusion occupancy, with no reproducible residual peak set.

The one human sample profiled under revumenib shows the oncoprotein reduced to undetectable levels 1. That is the falsifier condition for the fusion-occupancy half of the hypothesis, in the only relevant material anyone has produced. What it does not falsify is the broader idea the hypothesis is reaching for, that a residual occupied set maintains output at saturating drug — because a residual occupied set is exactly what was found, marked by ENL instead of by the fusion.

Two caveats before anyone treats this as settled. First, this sample is a lineage-switched sample, and lineage switching is itself associated with reduced oncoprotein levels independent of drug 1, so the undetectable oncoprotein may be a property of the switched state rather than of drug saturation. Second, 'undetectable' in a primary-sample chromatin profile is a sensitivity statement. The hypothesis should be revised rather than discarded, and this beat does not own that node — the finding is reported for the owning Queen rather than edited in.

The countermeasure class is already in the graph. Agents that evict the driver by a route independent of the menin pocket — catalytic KAT6/KAT7 inhibition, which rapidly evicts the MLL fusion from chromatin and overcomes both genetic and non-genetic menin-inhibitor resistance 3 — attack the occupancy directly rather than the interface. A YEATS-domain inhibitor or ENL degrader would be the mechanistically exact answer and is a real chemical class in development, though no study tests one against menin-inhibitor resistance. Bounded as of 2026-09-19 (raw eutils esearch): (YEATS OR ENL OR MLLT1)[Title/Abstract] AND (revumenib OR ziftomenib OR bleximenib OR "menin inhibitor" OR "menin inhibitors" OR "menin inhibition")[Title/Abstract] returns 3 records, and (ENL OR YEATS)[Title/Abstract] AND menin[Title/Abstract] returns 7. All were read. Two of the three are this entry's own source in its journal and preprint versions (PMIDs 39472576, 38234854) and the third is a review of menin-KMT2A targeting that mentions MLLT1 only as a fusion partner (PMID 39887730). None administers a YEATS inhibitor or ENL degrader to a menin-inhibitor-resistant or menin-inhibitor-treated model. The gap is real and is now a counted, dated negative rather than an unbounded one.

The cheap first step is not a drug at all. It is to run ENL CUT&RUN alongside the KMT2A-N-terminus CUT&RUN in the saturating-occupancy experiment this graph has already designed (exp-residual-occupancy-cutrun-saturating-menin). That experiment currently specifies JUND occupancy gain as its redistribution control; adding ENL costs one antibody and would convert a single patient observation into a testable model.