MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• The safety argument rests on AF9 being dispensable, and in human stem cells it is not: MLLT3/AF9 is required for maintenance of transplantable human HSPCs and its stabilisation expands them more than 12-fold (PMID 31776511). Paralogue cross-reactivity for an ENL YEATS ligand or degrader is therefore a stem-cell toxicity risk in the exact compartment an infant needs to rebuild, and no counter-screen has been run.
• Paralogue compensation is the obvious resistance route: AF9 shares the fold and the hub, is dispensable at baseline, and could be upregulated. Nobody has looked for AF9 upregulation after ENL loss, which is the first resistance experiment to run.
• Reader-pocket occupancy may be blocking a bypassed step. In an MLL fusion the MLL moiety supplies a constitutive PAF1 tether that circumvents H3 competition for ENL (PMID 29217648), so the YEATS acyl-lysine contact that an inhibitor competes with may not be load-bearing in the fusion context - while the PAF1 surface, which the published YEATS mutants also destroy, may be.
• Reader-pocket occupancy competes with an abundant endogenous ligand (acetylated histones) that is present at high local concentration, so achieving functional displacement in cells typically needs far better potency than the biochemical number suggests.
• gnomAD constraint is strong (pLI 1.0, LOEUF 0.330, mis_z 3.47), so human heterozygous loss is selected against; the reassuring DepMap mean of -0.006 comes from immortalised lines.
• A degrader removes the whole protein including the AHD, so it also removes ENL's normal roles in transcription elongation - a broader perturbation than a reader-pocket inhibitor and therefore a broader toxicity risk.
• The selectivity margin is thin: -0.132 is close to the noise floor for a 10-line comparison, and the claim survives on the published CRISPR work rather than on the DepMap number. If the published result is model-specific, the target weakens considerably.

1. Does occupying the ENL YEATS acyl-lysine pocket do anything in an MLL-fusion cell, given that the MLL moiety provides a constitutive PAF1 tether that circumvents H3 competition (PMID 29217648)? The published YEATS-mutant result removes the PAF1 surface as well as the histone surface and cannot separate them. A separation-of-function mutant, or a ligand profiled for PAF1 versus H3 displacement, is the missing experiment.
2. Why is ENL required when AF9 is not, given a shared fold and a shared hub architecture? Expression level, YEATS acyl-preference and AHD partner preference are the three candidate explanations and no published work separates them.
3. Does ENL degradation outperform ENL YEATS occupancy in a KMT2A::AFF1 model? 9DUR shows the ternary complex is achievable and the chemical-genetic result shows removal works, but the two modalities have never been compared head to head with matched exposure.
4. What is the actual affinity of the ENL YEATS domain for H3K27ac and H3K9ac? No number appears in any abstract we verified, and without it the competitive requirement for an occupancy inhibitor cannot be estimated.
5. In a KMT2A::AFF1 cell, is ENL engaged through its AHD by the fusion's AFF1 portion, and is that engagement what makes ENL essential, or is the YEATS reader function the load-bearing part? The YEATS mutant data suggest the reader matters, but the AHD has never been separately disabled in a KMT2A::AFF1 line.
6. Does ENL loss spare normal human haematopoietic stem cells? There is no mouse knockout phenotype in this dossier and gnomAD constraint is strong (LOEUF 0.330, mis_z 3.47).
7. What does an ENL-directed agent do to human haematopoietic stem cells through MLLT3 cross-reactivity? MLLT3/AF9 is required for maintenance of transplantable human HSPCs (PMID 31776511). No compound in this dossier has been counter-screened against MLLT3 or tested in a human HSPC engraftment assay, and this entry's 'AF9 is dispensable' framing came from cancer cell lines.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   MLLT1 is not DepMap common-essential (mean Chronos -0.006 across 1,258 lines) but falls to -0.162 across leukemia lines, -0.294 across 10 KMT2A-rearranged lines and -0.277 across 4 KMT2A::AFF1 lines, giving a lineage-controlled selectivity of -0.132 (rank 10 of 41), whereas its paralogue MLLT3/AF9 scores +0.059 (rank 33); gnomAD gives MLLT1 pLI 1.0, LOEUF 0.330, 11 observed versus 55.1 expected loss-of-function variants and mis_z 3.47; HPA classifies it as low tissue specificity, detected in all tissues.

   DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API; loss-of-function constraint via the gnomAD GraphQL API; normal-tissue expression via the Human Protein Atlas API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets Platform · Databases 2026
   ▸What this evidence cannot show

   Means were computed by us from per-line API values rather than read from a DepMap release table, and the release version is not stated by the API. Only 10 KMT2A-rearranged lines (4 KMT2A::AFF1) contribute, and a selectivity of -0.132 is close to the noise floor we estimated for a 10-line comparison; the claim survives mainly because two independent published CRISPR studies agree with it.

   ▸Evidence that argues against this (1)

   • A Chronos mean mixed across a KMT2A-rearranged subset and a comparator arm must be lineage-split before it is stated: the index arm is myeloid-enriched, so a difference between the two mixes fusion status with lineage. Ten or eleven index lines and four KMT2A::AFF1 lines also put wide intervals on every figure quoted. A mean of −0.006 across 1,258 lines falling to −0.277 in four KMT2A::AFF1 lines is a selectivity claim resting on four measurements. Oncofusion knowledge graph (internal analysis) 2026
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   ENL, but not AF9, is required in acute myeloid leukemia: CRISPR-Cas9 depletion of ENL is anti-leukaemic while AF9 depletion is not, and the ENL YEATS domain binds acetylated histone H3 and co-localises with H3K27ac and H3K9ac, with structure-based YEATS mutants that lose acyl binding showing reduced Pol II recruitment.

   ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia · Wan L, Wen H, Li Y, et al. · Nature 2017
   PMID 28241141DOI
   ▸What this evidence cannot show

   The models are AML rather than infant KMT2A::AFF1 B-ALL, and the abstract reports no numeric affinity for the YEATS-acyl-histone interaction, so no Kd should be attributed. 'AF9 not required' is a statement about the systems tested and does not exclude AF9 dependency in fusions where AF9 is itself the 3' partner.

   ▸Evidence that argues against this (1)

   • 'AF9 is dispensable' is a statement about immortalised leukaemia lines and it does not transfer to normal human stem cells. Calvanese et al. identify MLLT3/AF9 as a crucial regulator of human haematopoietic stem cells, highly enriched in human fetal, neonatal and adult HSCs and downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human HSPCs in culture, while stabilising MLLT3 enabled more than 12-fold expansion of transplantable HSCs giving balanced multilineage reconstitution in primary and secondary recipients; overexpressed MLLT3 localised to active promoters and sustained H3K79me2. So the paralogue this entry treats as the safe, dispensable comparator is an essential human HSC maintenance factor. For a project contemplating an ENL YEATS ligand or a CRBN degrader, that makes paralogue cross-reactivity a stem-cell toxicity risk rather than a mere selectivity inelegance, and it means any ENL agent needs an explicit MLLT3 counter-screen and a human HSPC engraftment assay before it goes near an infant. Calvanese V et al. 2019
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   A genome-scale CRISPR screen in an MLL-AF4-positive line identifies ENL as specifically required in vitro and in vivo; chemical-genetic targeted degradation of ENL suppresses both Pol II initiation and elongation, and an intact YEATS reader domain is essential for leukaemic growth.

   Transcription control by the ENL YEATS domain in acute leukaemia · Erb MA, Scott TG, Li BE, et al. · Nature 2017
   PMID 28241139DOI
   ▸What this evidence cannot show

   Chemical-genetic degradation uses an engineered degron rather than a drug, so it establishes that removing ENL works without establishing that a drug-like degrader will. The screen line is a cell line, not a primary infant sample. No numeric affinity is reported.

   ▸Evidence that argues against this (1)

   • The YEATS reader requirement may not hold in the one context this project cares about - an MLL fusion - because the fusion supplies a bypass. Hetzner et al. show that ENL overcomes polycomb silencing by recruiting PAF1 via the YEATS domain, that PAF1 is responsible for ENL's antirepressive activity and determines the transforming potential of MLL-ENL, and critically that **H3 and PAF1 COMPETE for the ENL interaction, whereas the MLL moiety provides a constitutive PAF1 tether allowing MLL fusions to circumvent H3 competition**. If PAF1 recruitment in an MLL-fusion cell is delivered constitutively through the MLL moiety rather than through acyl-histone reading, then occupying the YEATS acyl-lysine pocket blocks the wrong step, and the 'intact YEATS domain is essential' result in E3 - obtained by mutating the domain, which also removes the PAF1 surface - does not distinguish loss of histone reading from loss of PAF1 binding. The same paper shows YEATS mutations found in Wilms tumour and AML act as GAIN of function by favouring PAF1 over H3, which is the mirror image of the same competition. This is the strongest available argument for preferring degradation (9DUR) over YEATS occupancy, and it should be read alongside this entry's existing degrader case rather than against it. Hetzner K et al. 2018
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   ChEMBL v34 target CHEMBL4295801 (Protein ENL) carries 144 activity rows at pChEMBL >= 6 with a best Ki of 56 nM (CHEMBL4211714) across ENL-DOT1L PPI peptidomimetics, benzimidazole-amide YEATS binders and triazolopyridine-amides, and has no curated mechanism-of-action drug.

   ChEMBL database version 34, target CHEMBL4295801 (Protein ENL): target_search, get_bioactivity and get_mechanism queries · EMBL-EBI ChEMBL · ChEMBL 2026
   ▸What this evidence cannot show

   Distinct-compound counts and the 'best' value are page-local because of the 25-row API limit, so the best Ki is the best within a sampled page rather than across the whole target. Activity rows tagged INHIBITOR do not imply a clinical candidate; none is curated here.

   ▸Evidence that argues against this (1)

   • A ChEMBL activity-row count measures how much medicinal chemistry has been DONE, not how tractable the target is, and the best reported affinity belongs to the most optimised compound in whichever series someone chose to pursue. Zero rows means nobody tried; thousands of rows means a target had a decade of industrial attention. 144 rows spanning three distinct chemotypes is genuinely better evidence of tractability than a single series would be, and it still does not address whether occupying the YEATS pocket removes what ENL does — this graph records ENL persisting at target loci after the fusion and menin are undetectable. Journal of Clinical Oncology 2025
5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   The ENL YEATS domain has extensive verified structural coverage: with histone H3K27ac (5J9S, 2.70 A), with acetyllysine (6HPZ, 2.30 A), with the chemical probe SGC-iMLLT (6HT1, 2.10 A), with compound 94 (6HT0, 1.80 A), with a further inhibitor series (6HPW 1.90 A, 6HPX 2.30 A, 6HPY 2.00 A) and with piperazine-urea and benzimidazole-amide series (6T1I, 6T1J, 6T1L, 6T1M, 6T1N, 6T1O; 1.80-2.05 A); and a CRBN:degrader:ENL YEATS ternary complex is solved by cryo-EM at 2.90 A (9DUR). Two identifier corrections: 5J9T is the NuA4 core and not ENL YEATS, and 4TMP is an AF9 YEATS structure rather than an AHD structure.

   RCSB PDB entries 5J9S, 6HPW, 6HPX, 6HPY, 6HPZ, 6HT0, 6HT1, 6T1I, 6T1J, 6T1L, 6T1M, 6T1N, 6T1O, 9DUR and 4TMP, with per-entity UniProt accessions, ligands, methods, resolutions and modelled residue ranges resolved against the RCSB search and data GraphQL APIs · RCSB Protein Data Bank · RCSB PDB 2026
   ▸What this evidence cannot show

   All identifiers, resolutions and contents were read from the RCSB API in this session rather than recalled, which is why the two corrections could be made. None of these structures contains a KMT2A fusion protein. No numeric affinity for the YEATS-acyl-histone interaction appears in any abstract we verified, so the Kd field for that interaction is deliberately left null.

   ▸Evidence that argues against this (1)

   • Counting PDB entries measures how tractable a protein was to CRYSTALLISE, which correlates with being small, ordered and well-behaved rather than with being druggable. What decides design value is whether the deposited density covers the site that matters, at a resolution that supports modelling, in the relevant state — and this graph has repeatedly found structures described in the direction that overstates what is resolved. Extensive YEATS coverage is coverage of one 100-residue reader module of a 559-residue protein, and ENL's scaffolding function lies outside it. RCSB PDB 2026
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Beyond its role as a KMT2A fusion partner, MLLT1 carries recurrent activating mutations in its YEATS domain in Favourable Histology Wilms tumour, where the mutant protein binds acetylated histone tails differently and tumours show increased MYC and HOX dysregulation. So the domain this graph proposes to drug is an oncogenic driver in a second paediatric malignancy, by a mechanism that requires no fusion and no KMT2A.

   MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours · Nature Communications 2015
   PMID 26635203DOI
   ▸What this evidence cannot show

   Abstract read by the coordinator on 2026-09-19; full text not read, so the mutation spectrum and recurrence frequency are not recorded. Wilms tumour is a kidney malignancy and this is an analogy to the leukaemia biology, not an import - see `fusion-family-mllt1-yeats-wilms-tumour`.

   ▸Evidence that argues against this (1)

   • The Wilms mutations are activating and alter what the domain binds; an inhibitor abolishes binding. The paper therefore supports the domain being consequential and not that its loss is tolerated, which is the question the phase-2 dossier turns on. Journal of Molecular Biology 2022

• ← regulatesKAT2A / GCN5 - the SAGA catalytic subunit that reaches this disease through its complex rather than through its own symbol, and whose only chemical tool degrades its paralogue too

  KAT2A/KAT2B acetylation of ENL; degradation displaces ENL from target loci (preprint)

• ← bindsAFF1 / AF4 — domain architecture and residue coordinates

  same 761-775 motif binds the ENL ANC1 homology domain; inferred from AHD conservation, not separately solved

• ← related toThe neonatal window — the state in which an MLL fusion can transform, bounded at both ends

  MLL-ENL initiation efficiency peaks neonatally and adult HSCs are intrinsically protected

• ← related toAF10/MLLT10 fusions drive aberrant self-renewal of non-stem progenitors — found only by opening the paper

  ENL is the route: its YEATS domain binds MOZ/MORF and that contact is critical for CALM-AF10 transformation

• part of →The neonatal window — the state in which an MLL fusion can transform, bounded at both ends

  MLL-ENL is the fusion in which the neonatal window was measured

• regulates →Retained fetal programme — the infant-versus-adult stem cell difference, and the reason KMT2A::AFF1 needs no second mutation

  SKIDA1 sustains MLL::ENL-expressing progenitors during neonatal stages and promotes B-lineage priming

• ← depends onPro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on

  the KMT2A-rearranged B-lineage half is more MLLT1-dependent (-0.483) than the myeloid half (-0.223)

• ← related toMechanism class 4 — condensate-driven transcriptional rewiring (NUP98-r, EWSR1::FLI1)

  Normality of the SEC condensate (Guo 2020, PMID 32270036): ENL's IDR initiates SEC droplet formation and AFF4 fluidises them during ordinary serum-induced transcription, so condensate formation does not distinguish the leukaemic state.

• ← related toAnti-AF9 antibodies see three proteins, not two - and the third is an internal-promoter isoform discovered in 2025

  MLLT1 carries the same internal promoter but it is inactive in the haematopoietic lineage, making anti-ENL reagents cleaner than anti-AF9 in leukaemia

• ← related toAnti-ENL antibodies are the cleanest partner reagent in this disease and sit on top of the worst confound

  wild-type ENL is an independent dependency at the same loci, so pooling is causally loaded here

• ← bindsBlocking where DOT1L binds instead of what it does - the modality that removes the mark only at fusion targets

  ENL AHD pocket is the drugged interface

• ← related toThe DOT1L-AF10 octamer - the second route to H3K79 methylation, required in MLL-AF10 and absent from KMT2A::AFF1

  ENL YEATS-MOZ complex recruits AF10 fusion/DOT1L complexes to chromatin

• ← bindsAFF3 (LAF4) — the AFF-family scaffold of SEC-L3, and a KMT2A fusion partner in its own right

  SEC-L3 contains ENL/MLLT1, the same partner AFF1 and AFF4 bind

• ← bindsRNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once

  ATM-phosphorylated ENL binds the PRC1 E3 module via BMI1 - canonical PRC1, wild-type ENL, DNA-damage response, NOT a fusion contact

• ← bindsSUPT16H (SPT16) - the large FACT subunit: pan-essential, an anti-dependency in KMT2A-rearranged lines, and drugged in MLL-r leukaemia by a compound that works through p53

  ENL interacts with FACT and is required for FACT deposition over cis-regulatory elements - shown in colorectal cancer, not leukaemia.

• ← bindsFACT (SPT16-SSRP1) - the chromatin arm of transcription elongation, and a clean negative result for the KMT2A::AFF1 interactome

  ENL interacts with FACT and is required for its deposition at cis-regulatory elements - colorectal cancer, wild-type ENL.

• ← bindsThe ENL AHD to AFF1 contact: asserted throughout this graph, structurally unsolved, and represented only by an AF9 chimera measured at KD 0.17 nM

  ENL AHD, asserted contact with no structure

• binds →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)

  ENL, the acyl-histone reader that outperformed its own paralogue as a target

• ← supportsWhich leukemia co-dependencies survive uncertainty? (run, with p-values)
• ← analogous toThe same reader domain, mutated instead of fused, causes a childhood kidney tumour
• ← related toDOT1L is widely framed as a transcription-elongation factor, but the one direct test found in erythroleukaemic cells reported a role in initiation - in a non-KMT2A-rearranged line, so it is a counter-lead for the elongation model, not a refutation

  ENL depletion reduced TBP occupancy alongside DOT1L

• ← related toENL's nuclear annotation has no citation at all, and every picture of ENL in a nucleus is of a mutant or a fusion, never the wild-type protein

  localisation record for ENL: an uncited nuclear annotation and a condensate literature entirely about mutants

• binds →H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search

  ENL YEATS reads H3K9/K18/K27ac and is retained in 84.1% of KMT2A::MLLT1 patients

• ← bindsH3K9ac - the mark KMT2A fusions pile up on their own targets, the one the AF9 reader actually binds, and the one a DOT1L inhibitor strips off first

  ENL YEATS also reads H3K9ac and is displaced from target loci when acetylation is removed

• related to →MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is

  Counter-evidence (Calvanese 2019, PMID 31776511): MLLT3/AF9 governs human haematopoietic stem-cell self-renewal and engraftment; depletion prevents maintenance of transplantable human HSPCs. 'AF9 is dispensable' holds in leukaemia lines only, so paralogue cross-reactivity for an ENL ligand or degrader is a stem-cell toxicity risk, not a selectivity nicety.

• related to →PAF1 — pan-essential subunit of a complex the fusion needs, where the window is in the interface and not in the protein

  Counter-evidence (Hetzner 2018, PMID 29217648): H3 and PAF1 compete for ENL, and the MLL moiety of an MLL fusion supplies a constitutive PAF1 tether that circumvents H3 competition. YEATS acyl-pocket occupancy may block a step the fusion has already routed around, and the published YEATS mutants destroy the PAF1 surface as well as the histone surface.

• ← part ofThe KMT2A::MLLT1 chimeric protein: exactly what survives the join on each side, in residue numbers

  3' contribution: YEATS 1-138, disordered 147-484, AHD (UniProt Q03111)

• ← part ofHow a spliced fusion works: the break lands in front of MLLT1, the gene is never cut, and there is nothing left to make a reciprocal product from

  break lands 5' of MLLT1 exon 1; the gene itself is never interrupted

• ← part ofKOPN-8 (CVCL_1866): the field's default KMT2A::MLLT1 line, and its fusion protein has no YEATS domain

  fusion lacks the MLLT1 YEATS domain

• ← part ofThe ENL YEATS acetyl-reader inside KMT2A::MLLT1: what it reads, what it does, and why both control arms carry it

  ENL YEATS domain, UniProt Q03111 (559 aa), reads H3K9ac/K18ac/K27ac

• ← related toThe KMT2A::MLLT1 mechanism sweep: what was searched, what was read and not used, and the three retrieval traps that would have produced confident wrong answers

  MLLT1 internal promoter drives a YEATS-devoid isoform that is inactive in haematopoiesis and AML

• ← bindsABI1 (Abl interactor 1 / e3B1) — WAVE-complex cytoskeletal adaptor, KMT2A partner, and an ENL-binding protein

  ABI1 binds ENL via an internal ENL region and a composite ABI1 SH3-containing motif

• ← related toKMT2A::MLLT1 is high-risk in childhood AML and the best-outcome cell in childhood T-ALL: the partner effect changes sign with lineage

  ENL/MLLT1 prognostic direction depends on lineage

• ← regulatesATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners

  phosphorylates ENL at conserved SQ sites

• ← regulatesATM phosphorylates ENL at conserved SQ sites and flips it from elongation to Polycomb repression - on sequence every KMT2A::MLLT1 fusion keeps

  ATM-gated switch from elongation to PRC1 repression

• ← related toPhosphosite counts for the five 3' partners: the atlas beats UniProt 1.4-6.0x, and the retained/lost split is completely different for each partner

  23 observed phosphosites, all retained

• ← related toNothing connects ENL YEATS binding or ENL condensates to phosphorylation: zero records, and what that means for the phase-2 dossier

  no observed phosphosite inside the ENL YEATS domain

• ← related to"ENL" returns 1,109 PubMed records of which about 30% are the protein: a measured alias-precision failure

  ENL token collides with three unrelated literatures

• ← bindsKMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution

  ENL carries the same AHD (PF17793)

• ← part ofImport class 2: AHD-dependent mechanism, which cannot transfer because KMT2A::AFF1 has no AHD

  ENL carries the same AHD

• ← bindsAFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L

  ENL carries the same AHD

• ← related toPhase-2 dossier: the ENL YEATS pocket - two co-crystals, nanomolar chemistry, and a co-dependency that only appears inside leukaemia

  readiness layer on top of the ENL biology entry

• ← related toPhase-2 dossier: the non-small-molecule modalities - degraders first, and the honest limits of each

  ENL is the target where degradation may beat occupancy; the head-to-head is the cheapest decisive experiment

• ← related toThe super elongation complex, sampled from the RNA side: ELL, ENL, CDK9 and cyclin T1 are all in the proximity record - ELL2, EAF1/2, AF9 and AF10 are at zero

  MLLT1/ENL recovered by seven baits

• ← co-occurs withRSBN1 / KDM9 (Q5VWQ0) - an H4K20me2/me3 demethylase in the AFF4 proximity record, and the only read-queue partner that is a chromatin enzyme at all

  Skucha 2018 seven-bait MLL-fusion AP-MS: recovered by MLL-EEN only, p = 0.0756, 5|7 spectra, and ABSENT from the MLL-AF4 column

• ← related toThe paper's four comparison loci, marks read against FISH calls: the H3K9 mark response agrees with the cytogenetic response at two loci and contradicts it at two - the mark is neither necessary nor sufficient

  H3K9me1 +1.38x and H3K9me2 +1.43x over the gene body, at a locus the paper scores non-responsive

• ← related toRe-bound at full text: no study of MLLT1/ENL function in cerebellum or developing brain exists, and 10 of the 22 full-text hits are congress abstract books - the weakest-bounded absence in the corpus is now the best-bounded of the four ENL ones

  no full-text record of ENL function in cerebellum or developing brain, the tissue of its highest expression

• ← related toAFF1 occupancy does not distinguish fusion-occupied promoters from wild-type KMT2A promoters in primary infant KMT2A::AFF1 - reproduced at promoter resolution, and the corpus should stop reading a partner ChIP as a fusion readout

  ENL is the discriminating cofactor, 1.9-2.8x

• ← related toENL is the only elongation cofactor that separates fusion-occupied promoters from wild-type KMT2A promoters by more than the H3K4me3 negative control does, in primary infant KMT2A::AFF1

  ENL 1.9-2.8x at fusion promoters, 3.5-5.5x null on top promoters

• ← related toIn drug-naive primary infant KMT2A::MLLT1 B-ALL, menin is as enriched as the fusion N-terminus at the top fusion promoters (2.73x vs 3.12x over an accessibility reference) while the wild-type C-terminal reporter sits at background (1.10x)

  ENL is enriched 11.76x at the same promoters

• ← related toENL redistributes rather than persists: it is the only channel that holds more of its signal at the myeloid-program peaks than at the B-lineage ones, by 2.06x in my instrument and 1.26x in the authors' own - and in absolute terms it falls further than menin does

  ENL is the channel that redistributes

• ← related toIn the HOXA-dead infant states IRX1 carries H3K4me3 and ENL while HOXA9/HOXA10 carry neither

  ENL at IRX1 at 4.4-6.5x while HOXA9 reads 0.000-0.109x

• ← inhibitsSGC-iMLLT - the MLLT1/MLLT3 YEATS chemical probe, and the 2026 paper that put it into KMT2A::AFF1 in vivo with a healthy-HSPC comparison

  competitive antagonist of the MLLT1 YEATS acyl-lysine reader pocket; co-crystal 6HT1

• ← related toSEC-L2 and SEC-L3 contain ENL and AF9 exactly as SEC does, so AFF2 and AFF3 sit in complexes built around the same acyl-lysine readers as the index fusion's partner - and both entries carry no epigenetics annotation at all

  ENL is a stoichiometric partner in SEC-L2 and SEC-L3 as well as in SEC, which bears on YEATS-inhibitor selectivity

• part of →SEC-L2 — the AFF2-scaffolded super-elongation-like complex: P-TEFb plus ENL and AF9, and NO ELL

  ENL is a shared subunit of SEC-L2 (MudPIT, endogenous co-IP, size exclusion)

• part of →SEC-L3 — the AFF3-scaffolded complex, and the only SEC-family member with a known physiological job: genomic imprinting and X inactivation

  ENL is a shared subunit of SEC-L3

• part of →SEC — the AFF1/AFF4-scaffolded super elongation complex, the particle KMT2A::AFF1 is a permanent subunit of

  ENL is a YEATS-reader subunit of SEC, and of SEC-L2 and SEC-L3 as well

• ← depends onTwo surfaces, two jobs: the AHD picks the scaffold and the YEATS pocket reads the histone — so a YEATS ligand cannot ask which of the three SEC-family complexes it is disabling

  ENL carries both surfaces; only one of them is druggable today

• ← testsMeasure the one number the whole YEATS-selectivity argument turns on: what fraction of ENL and of AF9 is in SEC, in SEC-L2, in SEC-L3 and free — with an exchange control, because the question may not be well posed

  ENL pool partition across the AFF scaffolds

• ← related toMLLT3 runs normal stem-cell self-renewal and is required in essentially no leukaemia line — the inverted case

  AF9/MLLT3 and ENL/MLLT1 both sit in three distinct SEC-family complexes controlling different gene subsets (PMID 22547686), so overexpression or knockdown of either changes the stoichiometry of three complexes at once - and YEATS-devoid internal-promoter isoforms are a confound for every MLLT1/MLLT3 expression or dependency measurement, since the ENL YEATS-MOZ contact is what maintains fusion chromatin retention (PMID 37031220)

• ← related toMenin inhibition is a reshuffle, not a subtraction: four proteins are documented to GAIN chromatin or persist under the drug, and none of them is the fusion

  ENL is the fourth case - persistence at target loci after the oncoprotein is undetectable

• ← bindsPIP4K2A - the lipid kinase at a genome-wide childhood-ALL susceptibility locus, whose product is the ligand a PHD finger reads

  PIP4K2A-bait AP-MS in HEK293T and U2OS - the bait set is five SEC subunits, so probably one contact

• ← bindsEPB41L3 / DAL-1 - a membrane-skeleton tumour suppressor that binds and modulates two arginine methyltransferases, and whose own promoter methylation is a clinical test

  EPB41L3-bait AP-MS, BioPlex 3.0 HEK293T

• ← depends onENL stays after the fusion leaves — an epigenetic lesion that outlives the protein that made it

  ENL is the persisting cofactor that marks the lesion

• ← related toMLLT1 (ENL) refutes the YEATS parallel: the reader is retained in 84% of patients and is required for leukemogenesis

  ENL YEATS domain aa 1-138 retained in the fusion

• ← related toDNTT (TdT) - a real gene the graph calls by its enzyme nickname, and TdT-negativity is 100% KMT2A-rearranged in the largest paediatric series

  partner-specific TdT-negative phenotype, recorded in neither the gene nor the fusion entry