Oncofusion

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Proteinstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q5-interactome4

MYB — rank 17 of 17,728 for KMT2A selectivity, and the only node in this beat where partial, transient suppression eradicated leukaemia without stopping normal blood production

also called MYB · c-Myb · c-myb · Transcriptional activator Myb

MYB is the transcription factor the MLL-AF9 fusion uses to keep leukaemia cells renewing themselves. Turning it down only partly, and only for a while, wiped out aggressive leukaemia in mice while normal blood production carried on — which is about as clean a therapeutic window as this field has ever produced.

The same thing, for a scientist

MYB (P10242, 640 aa) is the haematopoietic transcriptional activator with three myb-type helix-turn-helix repeats (aa 35-86, 87-142, 143-193), a transcription activation domain at aa 275-327 and a negative regulatory domain at aa 328-465 [E1]. Using genetically defined mouse models, transcriptional profiling and an inducible RNAi platform, Zuber et al. showed that **MLL-AF9 maintains leukaemia by enforcing a Myb-coordinated programme of aberrant self-renewal**, and that **partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis** [E2]. The dependency data are the most extreme positive result in this beat: MYB ranks **17 of 17,728 (0.096th percentile)** with a difference of **-0.4746** (KMT2A-rearranged mean -1.9254 against other-leukaemia -1.4508) on a pan-essentiality of only **-0.3840** [E3]. Only MEN1 (rank 1) and KMT2A itself (rank 11) score higher, and MYB outranks CEBPA (25), BRD9 (39), SPI1 (43), EP300 (108) and DOT1L (184). **Classification: downstream effector and dependency, not an interactor** — MYB is a target *of* the fusion's programme, and nothing cited here places it in contact with the fusion protein.

What it looks like
Transcriptional activator Myb640 aa
R1 (myb-type HTH repeat 1)R1 (myb-type HTH repeat 1) · residues 35–86R2 (myb-type HTH repeat 2)R2 (myb-type HTH repeat 2) · residues 87–142R3 (myb-type HTH repeat 3)R3 (myb-type HTH repeat 3) · residues 143–193TAD (transcription activation domain)TAD (transcription activation domain) · residues 275–327NRD (negative regulatory domain)NRD (negative regulatory domain) · residues 328–4650200400600
loading AF-P10242-F1…
AlphaFold AF-P10242-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
Why 'partial and transient' is the load-bearing phrase

MYB is required for normal definitive haematopoiesis. A complete, permanent knockout would be expected to ablate blood production, and that is exactly why MYB has been treated as undruggable for thirty years.

The Zuber result changes the shape of that argument rather than removing it. Using an inducible RNAi platform they showed that partial and transient suppression was sufficient to eradicate aggressive AML in vivo without preventing normal myelopoiesis 2. The claim is about a dose-and-duration window, not about MYB being dispensable. The DepMap profile is consistent with such a window existing: pan-essentiality -0.384 across 1,208 lines is moderate, while the KMT2A-rearranged mean of -1.925 is close to lethal 3. The rearranged cells are in a far steeper part of the dose-response curve than everything else.

That is the classic definition of a therapeutic index, and it is worth saying plainly that no other node in this beat has one: PRC1.1 points the wrong way, DSIF and NELF are pan-essential or anti-dependencies, the EAF and ICE subunits are neutral, and EP300 and KDM1A are good but score behind MYB.

Interactor or effector?

Effector. Zuber et al. describe a Myb-coordinated programme that MLL-AF9 enforces; the readout is transcriptional profiling plus inducible knockdown, not co-immunoprecipitation 2. Nothing read for this entry places MYB in physical contact with a KMT2A fusion protein.

There is a separate, independent result showing the reverse direction of traffic: an enhancer RNA (Myrlin) from the -81 kb murine Myb enhancer recruits KMT2A/MLL1 to the Myb locus, and CRISPRi silencing of Myrlin reduced KMT2A occupancy, decreased CDK9 and Pol II binding and produced Pol II pausing in the Myb first exon/intron 4. That is wild-type KMT2A acting on Myb rather than the fusion, and it is the only place in this beat where a pausing readout appears in a KMT2A-relevant experiment at all — which is itself a comment on how thin the pausing literature is here.

So the graph should carry MYB as: downstream of the fusion programme, upstream of self-renewal, reciprocally connected to wild-type KMT2A through its own enhancer, and not an interactome member.

Cell type, cell state, localisation, epigenetic readout
AxisDocumentedWhere
Cell typeGenetically defined mouse MLL-AF9 AML; normal myelopoiesis as the sparing control; murine erythroid cells for the enhancer work24
Cell stateAberrant self-renewal; the Myb programme includes genes linked to leukaemia stem cell potential and poor prognosis in human AML2
SubcellularNucleus1
SubnuclearNot established-
Epigenetic readoutNone of its own - MYB is a sequence-specific transcription factor. At its own locus the readout is H3K4me3 deposited by KMT2A recruited via the Myrlin eRNA, plus CDK9 and Pol II occupancy and a pausing change in exon 14
LineageMyeloid. No KMT2A::AFF1 or B-lineage experiment, which matters because MYB's role in B-cell development differs from its role in myelopoiesis.2
Facts and figures
uniprotP10242
gene symbolMYB
protein nameTranscriptional activator Myb
length AA640
alphafold IDAF-P10242-F1
accession resolutionUniProt REST query gene_exact:MYB AND organism_id:9606 AND reviewed:true, run 2026-09-19; one reviewed hit; primary gene name read back as MYB and length 640 confirmed from the same fetched record.
classificationdownstream effector and dependency; NOT an interactor of KMT2A::AFF1
classification reasonthe evidence is transcriptional profiling plus inducible RNAi phenocopy, not a protein-protein interaction; MYB is enforced BY the fusion programme rather than binding the fusion
interaction evidence classinducible RNAi in genetically defined mouse models; transcriptional profiling; eRNA-mediated KMT2A recruitment at the Myb locus (separate system)
shown for fusionMLL-AF9 in mouse; nothing in KMT2A::AFF1 or B-lineage
epigenetic readoutnone of its own; at its own locus, KMT2A-dependent H3K4me3 with CDK9 and Pol II occupancy changes and Pol II pausing in exon 1 on eRNA loss
therapeutic windowpartial and transient Myb suppression eradicated aggressive MLL-AF9 AML in vivo without preventing normal myelopoiesis (PMID 21828272); the window is a dose-and-duration effect and no molecule exploits it
domains
R1 (myb-type HTH repeat 1)35.0R1 (myb-type HTH repeat 1): 35R2 (myb-type HTH repeat 2)87.0R2 (myb-type HTH repeat 2): 87R3 (myb-type HTH repeat 3)143.0R3 (myb-type HTH repeat 3): 143TAD (transcription activa…275.0TAD (transcription activation domain): 275NRD (negative regulatory …328.0NRD (negative regulatory domain): 328
aliases retired or alternate
[
  "c-Myb"
]
domains — the numbers behind the chart
[
  {
    "name": "R1 (myb-type HTH repeat 1)",
    "start": 35,
    "end": 86,
    "source": "UniProt P10242, fetched 2026-09-19"
  },
  {
    "name": "R2 (myb-type HTH repeat 2)",
    "start": 87,
    "end": 142,
    "source": "UniProt P10242, fetched 2026-09-19"
  },
  {
    "name": "R3 (myb-type HTH repeat 3)",
    "start": 143,
    "end": 193,
    "source": "UniProt P10242, fetched 2026-09-19"
  },
  {
    "name": "TAD (transcription activation domain)",
    "start": 275,
    "end": 327,
    "source": "UniProt P10242, fetched 2026-09-19"
  },
  {
    "name": "NRD (negative regulatory domain)",
    "start": 328,
    "end": 465,
    "source": "UniProt P10242, fetched 2026-09-19"
  }
]
localization
{
  "subcellular": "nucleus",
  "subnuclear": "not established"
}
essentiality
{
  "depmap_scan": "analyses/depmap-kmt2a-selective-scan-full",
  "pan_essentiality_all_lines": -0.384,
  "n_all_lines": 1208,
  "mean_kmt2a_rearranged": -1.9254,
  "mean_other_leukemia": -1.4508,
  "kmt2a_selectivity_difference": -0.4746,
  "rank": 17,
  "n_scanned": 17728,
  "percentile": 0.096,
  "interpretation": "the strongest positive dependency found in this beat; third only to MEN1 and KMT2A itself among genes this project tracks"
}
enumeration record count
{
  "query": "(MLL OR KMT2A) AND (MYB OR c-Myb)",
  "records": 65,
  "date": "2026-09-19"
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -1.9254,
  "chronos_mean_other_leukaemia": -1.4508,
  "difference": -0.4746,
  "pan_essentiality_all_lines": -0.384,
  "selectivity_rank": 17,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}
How this could bite us back
  • MYB is indispensable for normal definitive haematopoiesis. The entire case rests on a dose-and-duration window demonstrated with an inducible shRNA, which is the delivery modality least like a drug.
  • MYB is a transcription factor with three DNA-binding HTH repeats and no known pocket. There is no molecule to test the window with, and generating one is a multi-year problem.
  • The comparator leukaemia lines are themselves strongly MYB-dependent (-1.45), so 'selective' here means a steeper requirement rather than a unique one, and off-target haematological toxicity would be the first thing observed.
  • If menin inhibition already suppresses MYB, adding a MYB-directed agent buys nothing and doubles the myelosuppression.
  • Suppressing a self-renewal programme in an infant is not the same intervention as suppressing it in an adult, and no paediatric or B-lineage data exist for any of this.
Still open
  1. Is MYB as selectively required in KMT2A::AFF1 infant B-ALL as in MLL-AF9 AML? MYB's role in B-cell development differs from its role in myelopoiesis and the sparing result may not transfer.
  2. Is there any ligandable surface on MYB, or on a MYB-cofactor interface such as MYB-CBP/p300 KIX? The KIX domain is in this graph's gene-ep300 entry at aa 566-645, and a MYB-KIX disruptor would be the obvious indirect route.
  3. Does menin inhibition lower MYB, and if so is MYB suppression the mechanism by which menin inhibitors work? That would make MYB a pharmacodynamic biomarker rather than a separate target.
  4. How much partial suppression, for how long, is enough? The Zuber result defines a window without measuring its edges, and every therapeutic decision depends on where they are.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB P10242 (MYB_HUMAN, Transcriptional activator Myb) is 640 aa and annotates three myb-type helix-turn-helix domains at aa 35-86, 87-142 and 143-193 with H-T-H motifs at aa 63-86, 115-138 and 166-189, a region at aa 90-193 interacting with HIPK2 and NLK, a transcription activation domain at aa 275-327, a negative regulatory domain at aa 328-465 and a leucine zipper at aa 376-397.

    UniProtKB P10242 (MYB_HUMAN), Transcriptional activator Myb · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
    What this evidence cannot show

    Record fetched 2026-09-19; primary gene name read back as MYB and length 640 confirmed from the same fetched record, and every coordinate copied from it. The transcription activation domain annotation cites a 1990 primary paper that was not read here.

    Evidence that argues against this (1)
    • A domain map is of limited use for this target. The therapeutic result is a dose-and-duration effect from RNAi knockdown, not from occupying any of these domains, and the DNA-binding HTH repeats are the least tractable surface class in small-molecule drug discovery. Nothing in this architecture suggests a pocket. Zuber J et al. 2011
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    An integrative approach combining genetically defined mouse models, transcriptional profiling and an inducible RNAi platform showed that MLL-AF9 contributes to leukaemia maintenance by enforcing a Myb-coordinated programme of aberrant self-renewal involving genes linked to leukaemia stem cell potential and poor prognosis in human AML; partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis.

    An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance · Zuber J, Rappaport AR, Luo W, Wang E, Chen C, Vaseva AV, Shi J, Weissmueller S, Fellmann C, Taylor MJ, Weissenboeck M, Graeber TG, Kogan SC, Vakoc CR, Lowe SW · Genes and Development 25(15):1628-40 2011
    PMID 21828272DOI
    What this evidence cannot show

    Abstract fetched and read on 2026-09-19; full text not read. Mouse MLL-AF9 AML only - no human validation, no KMT2A::AFF1, no B-lineage, no paediatric material. 'Without preventing normal myelopoiesis' is a statement about a mouse under a specific inducible-RNAi dose and duration, and does not establish that any achievable pharmacological exposure would reproduce it. MYB is a transcription factor with no known ligandable pocket, so the therapeutic index demonstrated here has no molecule to exploit it.

    Evidence that argues against this (1)
    • MYB is indispensable for normal definitive haematopoiesis, and the entire safety claim rests on 'partial and transient'. Any real-world agent would have variable exposure across tissues and time, and the margin that an inducible shRNA delivers on demand is exactly what pharmacology is worst at reproducing. The DepMap pan-essentiality of -0.384 across 1,208 lines confirms MYB is broadly required - just less so than in KMT2A-rearranged cells. Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    In the project's genome-wide KMT2A-rearranged selectivity scan of 17,728 genes, MYB ranks 17 (0.096th percentile) with a difference of -0.4746 (KMT2A-rearranged mean -1.9254 against other-leukaemia mean -1.4508) and a pan-essentiality of -0.3840 across 1,208 lines. In the same scan MEN1 ranks 1 (-0.8656), KMT2A 11 (-0.5411), CEBPA 25 (-0.4377), BRD9 39 (-0.3896), SPI1 43 (-0.3850), EP300 108 (-0.2837), SUPT4H1 138 (-0.2642), AFF1 160 (-0.2472) and DOT1L 184 (-0.2310).

    Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap Chronos via Open Targets) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026
    What this evidence cannot show

    All rows read out of analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-19 in one pass. Eleven KMT2A-rearranged against 43 other leukaemia lines, AML-heavy, none infant-derived. A KMT2A-rearranged mean of -1.93 is deep enough that partial floor compression applies to the difference, and MYB was not permutation-tested individually.

    Evidence that argues against this (1)
    • MYB is required across haematopoietic lineages generally, and the comparator set here is other leukaemia lines - many of them also MYB-dependent at -1.45. The difference is real but the absolute requirement in the comparator group is already severe, so 'selective' here means 'even more required', not 'required only here'. That is a materially weaker statement than MEN1's, where the comparator mean is -0.40. Zuber J et al. 2011
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Myrlin, a long non-coding enhancer RNA originating from the -81 kb murine Myb enhancer, interacts with the KMT2A/MLL1 complex; CRISPRi silencing of Myrlin downregulated Myrlin and Myb without perturbing LDB1 occupancy or the Myb enhancer hub, and compromised KMT2A occupancy in the Myb locus, decreasing CDK9 and RNA Pol II binding and resulting in Pol II pausing in the Myb first exon/intron.

    An enhancer RNA recruits KMT2A to regulate transcription of Myb · Kim J, Diaz LF, Miller MJ, Leadem B, Krivega I, Dean A · Cell Reports 43(7):114378 2024
    PMID 38889007DOI
    What this evidence cannot show

    Abstract fetched and read on 2026-09-19; full text not read. **Murine erythroid differentiation, wild-type KMT2A, no fusion and no leukaemia.** Myrlin is a mouse lncRNA and the existence of a human orthologue is not asserted here. The pausing observation is a consequence of reduced KMT2A occupancy, not a fusion-driven phenomenon.

    Evidence that argues against this (1)
    • This result runs the opposite way from the Zuber model and the two should not be merged. Here KMT2A activates Myb; there MLL-AF9 enforces a Myb-coordinated programme. Wild-type KMT2A at the Myb locus in erythroid cells and a KMT2A fusion driving self-renewal in myeloid leukaemia are different systems, and treating the enhancer result as evidence that the fusion regulates MYB directly would be an over-read. Zuber J et al. 2011
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