Oncofusion

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Proteinstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q5d-interactome3

CREBBP (CBP) — binds the KMT2A transactivation domain, which no fusion keeps

also called CREBBP · CBP · CREB-binding protein · KAT3A

CBP is a coactivator that normal KMT2A grabs with a short stretch near its middle in order to switch genes on. Leukemia fusions cut KMT2A long before that stretch, so the fusion has to turn genes on some other way.

The same thing, for a scientist

CREBBP (Q92793, 2,442 aa) binds KMT2A through a direct interaction between the KMT2A transactivation domain (**aa 2829-2883**) and the CBP **KIX domain (aa 581-687)**, mapped by yeast two-hybrid discovery, in vitro binding, and single-residue substitution: five hydrophobic residues forming one face of an amphipathic helix in the KMT2A TAD are required. KMT2A transactivation is CBP-dependent, and the KMT2A TAD and phospho-CREB bind KIX cooperatively rather than competitively. Residue 2829 is far C-terminal to the KMT2A breakpoint cluster region (exons 8-13, approximately aa 1100-1400), so the TAD is absent from every leukemia-associated KMT2A fusion including KMT2A::AFF1. CREBBP is not a KMT2A-selective dependency; its difference between 11 KMT2A-rearranged and 43 other leukemia lines is **+0.103**, i.e. KMT2A-rearranged lines need it slightly *less*.

What it looks like
CREB-binding protein2,442 aa
KIX KIX domain (binds the KMT2A transactivation domain and phospho-CREB) · residues 581–68705001,0001,5002,000
loading AF-Q92793-F1…
AlphaFold AF-Q92793-F1 ↗
colourshape

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.

very high (90+)confident (70–90)low (50–70)very low (<50)
I have never read one of these pictures before

A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.

Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.

Anything in yellow sticks is a bound small molecule, which is usually the drug.

Go deeper
A precisely mapped interface on a domain that is always discarded

This is the best-mapped of the wild-type-only KMT2A contacts. The interaction narrows to KMT2A 2829-2883 against CBP 581-687, and single amino-acid substitutions identify five hydrophobic residues on one face of an amphipathic helix as critical 1. Adenovirus E1A, which inhibits CBP, blocks KMT2A-mediated transactivation, as do mutations in those residues — so the dependence is functional and not merely physical.

The cooperativity result is the interesting one: the KMT2A activation domain facilitates CBP binding to phosphorylated CREB, against the then-standard picture of transcription factors competing for limiting CBP 1.

Method: yeast two-hybrid screen, in vitro binding with purified components, point mutagenesis, transactivation reporter assays with E1A inhibition. Shown for: wild-type KMT2A. Which part of the fusion: none — aa 2829-2883 sits roughly 1,400 residues past every clinical breakpoint. CREBBP is not a member of the KMT2A::AFF1 interactome.

The consequence worth stating plainly

KMT2A::AFF1 is a potent transcriptional activator that has no transactivation domain of its own. The activation function of wild-type KMT2A lives at aa 2829-2883 and is deleted. Everything the fusion does to activate transcription is therefore contributed by the partner — the AFF1 C-terminal region and the SEC/P-TEFb machinery it brings — rather than by a retained KMT2A activation function.

That is the structural basis for the project's whole framing: the retained KMT2A N-terminus supplies targeting (menin, LEDGF, CXXC, PAF1C) and the partner supplies activation. This entry is the citation for the second half of that sentence being a deletion rather than an addition.

Dependency, including a number that points the other way

CREBBP mean gene effect is -0.091 across 1,208 lines with 10.8% depleted, and the KMT2A-rearranged difference is +0.103 — KMT2A-rearranged lines are slightly less CREBBP-dependent than other leukemia lines 2. Its paralogue EP300 runs the other way: mean -0.359, 33.3% depleted, and a difference of -0.284 (mean -0.997 in KMT2A-rearranged against -0.713 in other leukemia lines) 2.

That EP300 number is one third of the MEN1 benchmark (-0.866) and is not nothing, but it belongs to EP300 rather than to CREBBP and is not explained by the CBP-KIX interaction described here, which was mapped against CBP. It is recorded as an observation for someone else to chase, not as a claim.

Facts and figures
uniprotQ92793
gene symbolCREBBP
length AA2442
protein nameCREB-binding protein
alphafold IDAF-Q92793-F1
accession resolutionUniProt query gene_exact:CREBBP AND organism_id:9606 AND reviewed:true; primary gene name read back as CREBBP and length 2442 confirmed
interaction evidence classyeast two-hybrid, in vitro binding with purified components, point mutagenesis, reporter transactivation with E1A inhibition
shown for fusionfalse
druggabilityNot a target via this interaction. The interface does not exist in the fusion.
subnuclear localizationtranscriptionally active Pol II domains, in association with HYPOphosphorylated Pol II (PMID 10893273); the internal core of a subset of PML nuclear bodies, alongside nascent Pol II transcripts (PMID 9560216); and nuclear speckles ONLY when transcription is inhibited (PMID 10893273). The state-dependence is the finding: CBP's subnuclear address reports what the cell is doing rather than what CBP is.
localization shown for fusionNO. Written into this field rather than into data.shown_for_fusion because THIS ENTRY'S shown_for_fusion IS A BOOLEAN carrying the interactome meaning - false, i.e. no demonstrated contact between CREBBP and a KMT2A FUSION, since the CBP-binding transactivation domain at KMT2A 2829-2883 is not retained in any fusion. That value is left untouched. For the localisation question: measured 2026-09-21 with NCBI esearch, (CREBBP[tiab] OR CBP[tiab] OR CREB-binding protein[tiab]) AND (MLL[tiab] OR KMT2A[tiab] OR MLL-AF4[tiab] OR MLL-AF9[tiab] OR mixed lineage leukemia[tiab]) AND (localiz*[tiab] OR localis*[tiab] OR subcellular[tiab] OR nuclear body[tiab] OR nuclear bodies[tiab] OR speckle*[tiab] OR condensat*[tiab] OR nucleolar[tiab] OR immunofluorescence[tiab] OR compartment*[tiab]) returns 8 records, all title-checked off-topic for CBP protein localisation - KAT6A chimeras with NURF and MLL/COMPASS, MORF-CBP and MOZ-TIF2 fusion reports, MOZ in B-cell progenitors, a KIX 9aaTAD interaction study, taxane resistance, and the CALM-AF10 clathrin-binding domain. The MOZ/MORF hits are a reminder that CBP is itself a fusion partner in AML, in lesions that are not KMT2A. Operands: gene clause 10,239, gene AND fusion 142. Positive control through the identical shape with (MLLT1[tiab] OR ENL[tiab]) returns 23. Zero in titles and abstracts; supporting figures not searched (brief rule 80).
epigenetic readoutWRITER AND READER IN ONE PROTEIN, AND BOTH MODULES SURVIVE IN A KMT2A FUSION - which is why the absence of an epigenetics field here was the wrong kind of gap. CBP/CREBBP is a lysine acetyltransferase whose principal nucleosomal products are H3K18ac and H3K27ac, and its bromodomain reads acetyl-lysine; the paralogue EP300 is written in this graph with exactly that readout (gene-ep300: histone acetylation H3K27ac, H3K18ac via the HAT domain; the bromodomain reads acetyl-lysine) and CREBBP had no corresponding line. THE MARK IS MEASURED IN THE INDEX DISEASE CLASS, AND IT IS SELECTIVE. In MLL-rearranged AML, ATAC-seq places EP300 and CREBBP as core epigenetic regulators; knockout of EP300/CREBBP or treatment with the catalytic HAT inhibitor A-485 suppresses MLL-rearranged cell proliferation while MLL wild-type cells are uninfluenced; and the mechanism reported is BLOCKING THE MLL-r-BET COMPLEX FROM BINDING H3K27ac AT CRITICAL GENE LOCI, explicitly DISTINCT FROM GLOBAL HISTONE ACETYLATION, with the CDK4/RB/E2F axis downregulated MLL-r-specifically [E_q97_epi1]. That makes H3K27ac the load-bearing mark for this gene in this disease, and it makes the readout a LOCUS-SPECIFIC one rather than a bulk-acetylation one - which is the distinction that decides whether a HAT inhibitor could have a therapeutic index at all. AND THE FUSION IMPORTS THE WRITER. This entry's E1 counter-evidence already records that in t(11;16)(q23;p13.3) CREBBP is the 3' partner and MLL is fused in frame to the CBP bromodomain, HAT, E1A-binding and nuclear-receptor domains, and that swapping the CBP bromodomain for P/CAF or TAF(II)250, or the CBP HAT for P/CAF or GCN5, changes the phenotype - so the mark-writing and mark-reading modules are functionally load-bearing and not interchangeable. KMT2A::CREBBP is therefore one of the few KMT2A fusions that brings its own histone-mark WRITER, in contrast to the partners that bring only elongation machinery. WHAT IS NOT SHOWN: nothing read for this entry measures H3K18ac anywhere in a KMT2A background (CREBBP[tiab] AND H3K18ac[tiab] returns 0 corpus-wide, with CBP[tiab] AND H3K18[tiab] AND acetyl*[tiab] at 32 as the control), and nothing measures any acetylation mark in KMT2A::AFF1 B-lymphoid cells. The one KMT2A-specific measurement is MYELOID (rule 73).
domains
[
  {
    "name": "KIX domain (binds the KMT2A transactivation domain and phospho-CREB)",
    "start": 581,
    "end": 687,
    "pfam": "PF02172"
  }
]
contact on kmt2a
{
  "kmt2a_domain": "TAD (transactivation domain)",
  "kmt2a_residues": [
    2829,
    2883
  ],
  "retained_in_fusion": false,
  "reason": "roughly 1,400 residues C-terminal to the KMT2A breakpoint cluster region (exons 8-13, approx. aa 1100-1400)"
}
essentiality
{
  "depmap_common_essential": false,
  "chronos_mean": -0.0908,
  "n_lines": 1208,
  "fraction_lines_depleted": 0.1084,
  "chronos_mean_kmt2a_rearranged": -0.035,
  "chronos_mean_other_leukemia": -0.1382,
  "kmt2a_selectivity_difference": 0.1032,
  "n_kmt2a_rearranged_lines": 11,
  "n_other_leukemia_lines": 43,
  "benchmark_men1_difference": -0.8656
}
paralogue
{
  "gene_symbol": "EP300",
  "chronos_mean": -0.3585,
  "fraction_lines_depleted": 0.3328,
  "chronos_mean_kmt2a_rearranged": -0.9967,
  "chronos_mean_other_leukemia": -0.713,
  "kmt2a_selectivity_difference": -0.2837,
  "note": "recorded as an unexplained observation; EP300 is not the protein mapped to the KMT2A TAD in this entry's primary source"
}
localization
{
  "subcellular": "Nucleus, with an experimentally annotated cytoplasmic pool: UniProt Q92793 lists Cytoplasm and Nucleus, both at ECO:0000269.",
  "subnuclear": "THREE distributions of one protein, and which one you see depends on whether the cell is transcribing. (1) Transcriptionally active domains: a subpopulation of CBP/p300 sits at active sites, partially colocalised with Pol II and tightly associated with HYPOphosphorylated Pol II. (2) PML nuclear bodies: CBP, p300 and Pol II are present in a subset of them, and CBP is distributed through the body's INTERNAL CORE while PML is not. (3) Nuclear speckles - but only on transcriptional INHIBITION, which relocates CBP/p300 and Pol II into speckles. The third is the one most likely to be misquoted, because speckle residence is usually read as a sign of activity and here it is the opposite.",
  "how_shown": "confocal immunofluorescence with double and triple labelling against Pol II phospho-forms and PML, co-immunoprecipitation, and transcriptional inhibition (PMID 10893273); in vivo nascent-RNA labelling with CBP and PML co-staining (PMID 9560216); UniProt Q92793 SUBCELLULAR LOCATION comment.",
  "systems": "cultured human non-haematopoietic cells; no leukaemia and no KMT2A-rearranged cell has ever been used to localise CBP",
  "node": "localization-transcription-factories-pol2-clusters"
}
cell type
{
  "expressed_in": "Not resolved to a haematopoietic cell type here. CREBBP is broadly expressed and this entry's DepMap row shows 10.8 percent of lines depleted [E2], so it is neither restricted nor commonly essential.",
  "required_in": "Not required in KMT2A-rearranged leukaemia by any measurement in this entry - the DepMap mean is -0.0908 across 1,208 lines [E2] and the KMT2A contact it is famous for is to a transactivation domain no fusion keeps [E1]. The cell type where CREBBP STATUS matters is the B-ALL blast, and it matters through loss: CREBBP-inactivated B-ALL is selectively vulnerable to venetoclax-induced ferroptosis [E_q66_cell1].",
  "mutated_in": "RELAPSED paediatric ALL, and largely as a consequence of therapy: CREBBP is one of twelve drug-response genes enriched for relapse-specific alterations, at 65 percent prevalence in early relapse (9-36 months) [E_q66_cell1 counter-evidence]. The cell type is therefore the persistent clone that survived induction, not the diagnostic blast.",
  "how_shown": "isogenic human B-ALL lines with targeted drug screen, lipidomics and in vivo validation (PMID 40393984); whole-genome sequencing of 103 diagnosis-relapse-germline trios with ultra-deep serial sequencing (PMID 31697823); genome-scale CRISPR fitness (this entry's E2)",
  "nodes": [
    "cell-type-pro-b",
    "cell-type-pre-b"
  ]
}
cell state
{
  "maintains_state": "not established. No experiment shows CREBBP maintaining a cell identity in this disease.",
  "regulates_state": "THE LIPID AND OXIDATIVE-STRESS STATE. CREBBP-mutated B-ALL cells differ in cell cycle, metabolism, LIPID COMPOSITION and oxidative-stress response in a way that predisposes them to ferroptosis, and those differences are further dysregulated on acquiring venetoclax resistance [E_q66_cell1]. Small-molecule CREBBP inhibition reproduces the state in wild-type cells, which makes it an inducible state rather than a fixed genotype.",
  "state_at_relapse": "The RELAPSE-INITIATING PERSISTER state: CREBBP alterations are relapse-specific and peak in early relapse, and mathematical modelling places their acquisition in a clone that survived initial therapy and gained resistance mutations during treatment [E_q66_cell1 counter-evidence].",
  "state_dependent_localisation": "CBP's own subnuclear position is a readout of transcriptional state - active Pol II domains when transcription runs, speckles when it is inhibited [E_q66_loc1]. Any drug that globally suppresses transcription in a blast, which several agents in this graph do, relocates CBP as a side effect.",
  "how_shown": "lipidomics, oxidative-stress and ferroptosis readouts with pharmacological CREBBP inhibition in isogenic B-ALL (PMID 40393984); serial and single-cell sequencing with mutational-signature and clonal modelling (PMID 31697823); transcription inhibition with CBP/Pol II co-staining (PMID 10893273)",
  "nodes": [
    "cell-state-lipid-pufa-dependence",
    "cell-state-relapse-initiating-persister",
    "cell-state-apoptotic-priming-bcl2"
  ]
}
epigenetic bounded absence
{
  "claim": "H3K18ac is not named together with CREBBP in the title/abstract index at all, and no acetylation mark has been measured for CREBBP in a B-lineage KMT2A-rearranged system.",
  "date_measured": "2026-09-21",
  "tool": "NCBI esearch db=pubmed (eutils), querytranslation read back from every response",
  "queries": [
    {
      "query": "CREBBP[tiab] AND H3K18ac[tiab]",
      "querytranslation": "\"CREBBP\"[Title/Abstract] AND \"H3K18ac\"[Title/Abstract]",
      "count": 0,
      "role": "the approved symbol paired with the compact mark spelling returns nothing"
    },
    {
      "query": "CBP[tiab] AND H3K18[tiab] AND acetyl*[tiab]",
      "querytranslation": "\"CBP\"[Title/Abstract] AND \"H3K18\"[Title/Abstract] AND \"acetyl*\"[Title/Abstract]",
      "count": 32,
      "role": "THE CONTROL, and it shows the zero above is a NAMING artefact, not an absence of biology. The protein name plus the uncompacted residue spelling returns 32. CBP is itself a contaminated token (CREB-binding protein, but also C/EBP-adjacent usage and calcium-binding protein), so these 32 were not counted as support - the point is only that the instrument reaches this pairing in quantity."
    },
    {
      "query": "CREBBP[tiab] AND H3K27ac[tiab]",
      "querytranslation": "\"CREBBP\"[Title/Abstract] AND \"H3K27ac\"[Title/Abstract]",
      "count": 15,
      "role": "the mark that IS reachable under the approved symbol; PMID 38693103 is in this set and is the MLL-r paper cited here"
    },
    {
      "query": "CREBBP[tiab] AND MLL[tiab] AND acetyl*[tiab]",
      "querytranslation": "\"CREBBP\"[Title/Abstract] AND \"MLL\"[Title/Abstract] AND \"acetyl*\"[Title/Abstract]",
      "count": 5,
      "title_checked": "PMID 38693103 (the MLL-r AML EP300/CREBBP paper, cited here), 40921261, 34243013, 25740345 and 22199269 - the last a breast-cancer histone-modifier expression panel, i.e. off topic and reached because MLL appeared as a non-gene string. 1 of 5 on topic."
    },
    {
      "query": "CREBBP[tiab] AND enhancer[tiab] AND H3K27ac[tiab] AND lymphoma[tiab]",
      "querytranslation": "\"CREBBP\"[Title/Abstract] AND \"enhancer\"[Title/Abstract] AND \"H3K27ac\"[Title/Abstract] AND \"lymphoma\"[Title/Abstract]",
      "count": 0,
      "role": "run to test whether the well-known CREBBP-mutant lymphoma enhancer-acetylation literature is reachable in this shape; it is not, at four terms, which is a warning that this query form under-reaches rather than a statement about that literature"
    }
  ],
  "symbols_searched": [
    "CREBBP",
    "CBP",
    "H3K18ac",
    "H3K18",
    "H3K27ac",
    "MLL"
  ],
  "symbols_not_searched": [
    "KAT3A",
    "CBP/p300",
    "RSTS",
    "KMT2A",
    "MLL1",
    "H3K18Ac",
    "H3-K18"
  ],
  "absence_class": "naming-artefact-not-absence",
  "absence_class_basis": "The H3K18ac zero is produced by the mark spelling, not by the literature: the same pairing under CBP plus H3K18 returns 32. This is rule 71's shape on the MARK side rather than the gene side. Bounded by titles and abstracts only (rule 80).",
  "reopening_condition": "Any H3K18ac or H3K27ac ChIP/CUT&RUN in a KMT2A::AFF1 B-lymphoid line or patient sample, with or without A-485, reopens the B-lineage arm. A re-run of the H3K18ac question must use H3K18 and lysine 18 spellings alongside the compact form."
}
How this could bite us back
  • CREBBP/EP300 inhibitors are in clinical development for other indications; this entry is the reason not to expect a KMT2A-fusion-specific effect from them through a KMT2A-binding mechanism.
  • CREBBP is a recurrently mutated tumour suppressor in relapsed pediatric ALL, so an agent that lowers its function carries a plausible risk of selecting for the very lesion associated with relapse.
  • The actionable claim here inverts the usual one: you do not inhibit CREBBP to treat the leukaemia, you inhibit it to SENSITISE the leukaemia, because CREBBP inactivation predisposes B-ALL to venetoclax-induced ferroptosis and a small-molecule CREBBP inhibitor pharmacocopies the mutation regardless of genotype (PMID 40393984). That is a combination rationale, and its bite-back is that it deliberately induces a state that in patients arises as a therapy-driven resistance lesion.
  • The population carrying the biomarker is manufactured by prior treatment: CREBBP is one of twelve drug-response genes enriched for relapse-specific alterations, reaching 65 percent prevalence in early relapse (PMID 31697823). A CREBBP-status-directed strategy is therefore a relapse strategy by construction, and prevalence at diagnosis will not predict it.
  • Paralogue: this entry already flags CREBBP against EP300, and the localisation literature does not separate them - the load-bearing imaging study reports CBP/p300 together (PMID 10893273). A CBP-selective agent would be claiming a selectivity the compartment evidence cannot corroborate.
  • Compartment side effect: CBP relocates into nuclear speckles when transcription is INHIBITED (PMID 10893273). Several agents in this graph suppress transcription globally, so combination studies pairing them with a CBP-directed compound are pairing a drug with a target the first drug has already moved.
  • A-485 inhibits the catalytic activity of both p300 and CBP, and CREBBP/EP300 haploinsufficiency causes Rubinstein-Taybi syndrome in humans - a developmental disorder. Applying a catalytic HAT inhibitor to an infant targets the enzyme whose partial loss is a congenital syndrome, and the essential-function toxicity is therefore not hypothetical.
  • The mechanism is reading, not writing: the drug's reported effect is to stop the MLL-r-BET complex binding H3K27ac (PMID 38693103). That makes the pathway redundant with BET inhibition, so a CBP/p300 inhibitor and a BET inhibitor may not combine additively and cross-resistance between them is a predicted, testable liability.
  • CREBBP is itself a KMT2A fusion partner (t(11;16)) and a frequently mutated gene in relapsed ALL. An agent that removes CBP activity in a cell already selected for altered CBP dosage is acting on a moving target, and the direction of the alteration differs between patients.
Still open
  1. EP300 shows a -0.284 KMT2A-rearranged selectivity that CREBBP does not. Is that real, and if so is it connected to KMT2A biology at all or to something else the lines share?
  2. Does the reciprocal AF4::KMT2A product, which carries the KMT2A C-terminus including the TAD, bind CBP? Nobody appears to have asked, and it is a testable difference between the two derivative products.
  3. Wild-type KMT2A retains its TAD in every patient. Does CBP recruitment by the wild-type allele contribute to the expression of loci the fusion also occupies?
  4. Is the CREBBP-ferroptosis vulnerability present in infant KMT2A::AFF1 B-ALL specifically? The lineage is right and the fusion is unstated, and this graph already records infant KMT2A-rearranged ALL as the BCL2-dependent childhood subgroup - which would make CREBBP inhibition plus venetoclax a doubly motivated combination or a redundant one.
  5. Where is CBP in a KMT2A-rearranged blast, and is any of it in PML bodies? The PML body is this graph's compartment for a different fusion entirely, and CBP is the one protein reported to sit in its internal core.
  6. Does CBP's speckle relocation on transcriptional inhibition happen under a menin inhibitor? If it does, CBP occupancy measured after treatment reports the drug's effect on transcription rather than a change in CBP biology.
  7. Does A-485 or any p300/CBP HAT inhibitor work in KMT2A::AFF1 B-lymphoid cells? The one MLL-r selectivity result is myeloid and the drug is the only route to testing whether the H3K27ac-reading step is required in the index disease.
  8. Is the H3K27ac that the MLL-r-BET complex reads deposited by CREBBP, by EP300, or by both? A-485 cannot separate them and the knockouts in PMID 38693103 are reported jointly, so the paralogue question that decides which gene is the target is open.
  9. In KMT2A::CREBBP t(11;16), does the imported CBP HAT deposit H3K27ac at the fusion's own target loci? The fusion carries an intact writer and nobody has ChIPped the mark in that background - it is the one KMT2A fusion where writer import is structurally certain.
Every source behind this entry (6)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    MLL/KMT2A interacts directly with CBP, not with CREB, through KMT2A amino acids 2829-2883 (a transcriptional activation domain) and CBP amino acids 581-687 (the KIX domain); five hydrophobic residues on one face of an amphipathic helix in the KMT2A activation domain are critical; MLL transactivation is CBP-dependent and is blocked by E1A; and the MLL activation domain facilitates CBP binding to phosphorylated CREB.

    MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. · Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ · Molecular and Cellular Biology 2001
    PMID 11259575DOI
    What this evidence cannot show

    Abstract read in full; not full text. Discovery was a yeast genetic screen with an MLL fragment, and the mapping is on isolated domains and purified components, not full-length proteins in cells. No fusion protein is tested. The TAD boundary given (2829-2883) is the minimal region of interaction from this paper, and other papers define the MLL TAD slightly differently.

    Evidence that argues against this (2)
    • The title claim - CBP 'binds the KMT2A transactivation domain, which no fusion keeps' - is true of the TAD contact and false as a statement about CBP and KMT2A fusions. In t(11;16)(q23;p13.3), CREBBP is the 3' partner: MLL is fused in frame to the CBP bromodomain, HAT, E1A-binding and nuclear-receptor-coactivator-binding domains. Lavau et al. show that this fusion induces myeloid leukemia in mice preceded by a myelodysplastic phase, and that fusion of BOTH the CBP bromodomain and the HAT domain to the MLL amino portion is required for full transformation in vitro and sufficient for the leukemic phenotype in vivo. CBP is not merely a lost wild-type contact; in one recurrent KMT2A rearrangement it is the transforming module. Read: abstract in full, not full text. Lavau C et al. 2000
    • And the specificity of those CBP domains is functionally load-bearing rather than incidental. Santillan et al. swapped the CBP bromodomain for the P/CAF or TAF(II)250 bromodomains and the CBP HAT for the P/CAF or GCN5 HAT inside MLL-CBP: HAT substitution gave enhanced proliferation but lost the myeloid surface markers, and mice reconstituted with domain-swapped progenitors developed lymphoid disease and less frequent myelodysplasia. So CBP's chromatin-modifying chemistry determines the disease phenotype of a KMT2A fusion. An entry filed under 'not an interactor of the fusion' should carry that, because it is the strongest case in the beat that a CREBBP-directed agent has a KMT2A-rearranged indication. Read: abstract in full, not full text. Santillan DA et al. 2006
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset

    CREBBP has DepMap mean gene effect -0.0908 across 1,208 lines with 10.8% of lines depleted and a KMT2A-rearranged minus other-leukemia difference of +0.103; EP300 has mean -0.3585 with 33.3% depleted and a difference of -0.284 (mean -0.997 KMT2A-rearranged vs -0.713 other leukemia); MEN1 in the same lines is -0.866.

    DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API, with KMT2A-rearrangement status from Cellosaurus; per-gene recomputation for this beat · Broad Institute DepMap; Cellosaurus; Open Targets Platform; analysis run by this project · Database and derived analysis 2026
    What this evidence cannot show

    DepMap release version not stated by the API. Eleven KMT2A-rearranged lines; the EP300 difference of -0.284 at that n has not been permutation-tested here and should be treated as a lead rather than a result. CREBBP is recurrently mutated in relapsed ALL, which confounds any cell-line dependency reading.

    Evidence that argues against this (1)
    • The +0.103 CREBBP difference is read here as 'KMT2A-rearranged lines need it slightly less'. A knockout-screen difference of that size, on a gene depleted in only 10.8% of lines, is not evidence of non-requirement. Valerio et al. show MOF/KAT8 - a chromatin acetyltransferase with no KMT2A selectivity in this graph's own scan - is nevertheless required for MLL-AF9 leukemia maintenance in vivo, that its catalytic activity is required, and that the MYST inhibitor MG149 is antiproliferative in human KMT2A-rearranged lines. Read from the full text: the requirement does not run through Hoxa9/Meis1, and non-KMT2A lines are also MG149-sensitive. The general point for this entry is that a near-zero selectivity difference bounds selectivity, not requirement. Read: FULL TEXT via PMC5501293. Valerio DG et al. 2017
  3. E_q66_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    CBP is distributed to transcriptionally active domains and its position tracks the cell's transcriptional activity: a SUBPOPULATION of CBP and p300 is targeted to active sites of transcription and partially colocalises with hyper- and hypophosphorylated RNA polymerase II in discrete regions of variable size throughout the nucleus, the coactivators are tightly associated with HYPOphosphorylated but not hyperphosphorylated Pol II, and TRANSCRIPTIONAL INHIBITION RELOCATES CBP/p300 and Pol II INTO SPECKLES - and CBP, p300 and Pol II are all present in a subset of PML bodies.

    CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus. · von Mikecz A; Zhang S; Montminy M; Tan EM; Hemmerich P · J Cell Biol 2000
    PMID 10893273DOI
    What this evidence cannot show

    Confocal immunofluorescence plus co-immunoprecipitation in cultured human cells, not haematopoietic and not leukaemic. Only a SUBPOPULATION of CBP is at active sites, and the paper does not quantify the fraction. The antibodies used do not separate CBP from its paralogue p300 in every panel, which matters because this entry already flags CREBBP versus EP300 as a live identifier hazard. Speckle relocation is a response to a drug perturbation, so speckles are where CBP goes when transcription STOPS - the opposite of how speckle residence is usually read. Read: abstract only. Identifiers copied field by field from the efetch record fetched 2026-09-21, ArticleId anchored per brief rule 81.

    Evidence that argues against this (1)
    • An earlier and independent study puts CBP inside the PML body rather than merely overlapping it, and separates CBP from PML spatially: nascent RNA polymerase II transcripts exist within the PML nuclear body, PML and CBP colocalise, and CBP - IN CONTRAST TO PML - is distributed throughout the INTERNAL CORE of the structure. That is a finer-grained assignment than 'a subset of PML bodies' and it makes the PML body a candidate site of CBP function rather than an incidental overlap. LaMorte VJ; Dyck JA; Ochs RL; Evans RM 1998
  4. E_q66_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    CBP occupies the internal core of the PML nuclear body, a compartment that also contains nascent transcripts: a novel in vivo nucleic-acid labelling approach demonstrated nascent RNA polymerase II transcripts within the PML-containing nuclear body, PML and CBP colocalise within the nucleus, and CBP - unlike PML - is distributed throughout the internal core of the structure.

    Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body. · LaMorte VJ; Dyck JA; Ochs RL; Evans RM · Proc Natl Acad Sci U S A 1998
    PMID 9560216DOI
    What this evidence cannot show

    Cultured cells in 1998, with light microscopy at the resolution of the day; 'internal core' versus 'shell' is an optical distinction that later super-resolution work has revised for several nuclear bodies. Not haematopoietic, not leukaemic. The PML body is the compartment this graph already records for PML-RARA, a DIFFERENT fusion in a different disease, so any use of this result in the KMT2A context carries a lesion difference. Read: abstract only.

    Evidence that argues against this (1)
    • CBP is only in a SUBSET of PML bodies and the bulk of the functional pool appears to be elsewhere - at transcriptionally active domains with hypophosphorylated Pol II - and CBP moves into speckles when transcription is inhibited. So the PML-body pool is one of at least three distributions of the same protein, and which one dominates depends on the cell's transcriptional state at the moment of fixation. von Mikecz A; Zhang S; Montminy M; Tan EM; Hemmerich P 2000
  5. E_q66_cell1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In B-cell acute lymphoblastic leukaemia, CREBBP inactivation creates a lipid-metabolic vulnerability rather than a transcriptional one: a targeted drug screen in isogenic human cell lines identified venetoclax as the most potent agent against CREBBP-mutated B-ALL, acting through a NON-CANONICAL mechanism producing FERROPTOTIC rather than apoptotic death; CREBBP-mutated lines differ in cell cycle, metabolism, LIPID COMPOSITION and oxidative-stress response, predisposing them to ferroptosis, and small-molecule CREBBP inhibition pharmacocopies the mutation, sensitising B-ALL cells regardless of genotype to venetoclax-induced ferroptosis in vitro and in vivo.

    CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition. · Garcia-Gimenez A; Ditcham JE; Azazi DMA; Giotopoulos G; Asby R; Meduri E; Bagri J; Sakakini N; Lopez CK; Narayan N; Beinortas T; Agrawal-Singh S; Fung K; O'Connor D; Mansour MR; Alabed HBR; Jenkins B; Koulman A; Murphy MP; Horton SJ; Huntly BJP; Richardson SE · Nat Commun 2025
    PMID 40393984DOI
    What this evidence cannot show

    Human B-ALL, which is the right lineage for the index disease, but isogenic cell lines plus xenograft rather than primary infant KMT2A::AFF1 material, and KMT2A status is not stated. CREBBP mutation and pharmacological CREBBP inhibition are treated as equivalent, which is a strong assumption for a 2,442-residue scaffold with several separable domains. Ferroptosis versus apoptosis is assigned by pathway markers and rescue, not by a single decisive assay. Read: abstract only.

    Evidence that argues against this (1)
  6. E_q97_epi1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In MLL-rearranged AML, EP300 and CREBBP are core epigenetic regulators by ATAC-seq; EP300/CREBBP knockout or the HAT inhibitor A-485 suppresses MLL-rearranged cell proliferation while MLL wild-type cells are uninfluenced, the CDK4/RB/E2F axis is downregulated MLL-r-specifically, and the selective anti-leukaemic activity works by blocking the MLL-r-BET complex from binding H3K27ac at critical gene loci, distinct from global histone acetylation.

    PMID 38693103
    What this evidence cannot show

    Abstract fetched and read in full 2026-09-21; full text not read. MLL-rearranged AML - MYELOID, and the specific fusion is not named in the abstract, so this is a disease-class result and not a KMT2A::AFF1 result (rule 73). EP300 and CREBBP are treated together throughout and A-485 inhibits both, so nothing here separates the two paralogues; the graph already holds gene-ep300 with the same readout and the same paper is cited there at mark-h3k27ac E6. The MLL wild-type comparison is what carries the selectivity claim and its cell panel is not described in the abstract.

    Evidence that argues against this (1)
    • The counter-argument is inside the paper's own framing. A-485 is a catalytic p300/CBP HAT inhibitor and the authors report the effect as distinct from global histone acetylation, i.e. the selectivity is asserted at the level of which loci matter rather than at the level of the drug's target. A drug whose target is the acetyltransferase for one of the most abundant activating marks in the genome does not become locus-selective because its phenotype is; this graph's gene-crebbp E2 counter-evidence already records the opposite-direction case, MOF/KAT8, where an acetyltransferase with NO KMT2A selectivity in a knockout screen is nonetheless required for MLL-AF9 leukaemogenesis. Valerio DG et al. 2017
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