Oncofusion

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Proteinstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q5c-interactome2

MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

also called MEIS1 · Meis homeobox 1 · myeloid ecotropic viral integration site 1 protein · TALE homeodomain

MEIS1 partners with HOXA9 and sets how many leukemia stem cells a KMT2A fusion can make — turn it down and the disease loses its engine. Mice without it die before birth, which is the problem with treating it as a drug target.

The same thing, for a scientist

MEIS1 (O00470, 390 aa) is a TALE-class homeodomain transcription factor and the HOXA9 cofactor. It is an essential and rate-limiting regulator of MLL leukemia stem cell potential, required for both induction and maintenance of MLL transformation, and it quantitatively sets LSC frequency through self-renewal, differentiation arrest and cycling. It survives Holm correction as a MEN1 co-dependency at r = 0.468 across 54 leukemia lines. Meis1-deficient mouse embryos die by E14.5 with extensive haemorrhage and absent megakaryocytes, and MEIS1 is strongly constrained in humans (LOEUF 0.207).

What it looks like
MEIS1390 aa
MEIS N-terminal domainMEIS N-terminal domain · residues 108–1920100200300
loading AF-O00470-F1…
AlphaFold AF-O00470-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
Rate-limiting, not merely required

Meis1 is required for both the induction and the maintenance of MLL transformation, and — the more interesting claim — it is rate-limiting: it quantitatively sets leukemia stem cell frequency through effects on self-renewal, differentiation arrest and cycling 1. A rate-limiting regulator is a better target than a merely necessary one, because partial reduction should produce a proportionate effect rather than nothing until a threshold is crossed.

That same paper carries the complication. The Meis1 requirement runs through redundant Pbx2 and Pbx3, so the functional unit is the MEIS1–PBX interaction rather than MEIS1 alone. Structure-function dissection identifies two regions required for leukemia induction, the PBX-interaction motif and a C-terminal transactivation domain, with a key role for Hoxa gene activation 2.

MEIS1 is also not independent of HOXA9: HOXA9 knockdown in MLL-rearranged cells co-downregulates MEIS1 3. The output programme is a single circuit, and this graph should not treat HOXA9 and MEIS1 as two separate targets offering two separate shots.

It is one of the ten that survived correction

MEIS1 correlates with MEN1 at r = 0.468 (95% CI 0.198–0.691, permutation p = 0.0004, Holm p = 0.008) across 54 leukemia lines — seventh of the ten survivors, ahead of DPY30 and BCL2 4.

But the dependency itself is shallow. Mean Chronos is -0.053 across 1,258 lines with only 1.3% of lines depleted, and the leukemia mean is -0.090 5. MEIS1 is barely required by any line in the panel. The most likely explanation is expression: MEIS1 is expressed in few of the screened lines, and a gene that is off cannot be a dependency. That makes the MEN1 correlation harder to interpret rather than easier — it may be tracking which lines express MEIS1 at all, which is close to tracking lineage.

This is an important caution about the ten-survivor list generally. Surviving Holm correction says a correlation is unlikely to be noise; it does not say the correlation reflects a shared process rather than shared expression.

The tolerability problem is severe

Meis1-deficient mouse embryos die by embryonic day 14.5 with extensive haemorrhage, absent megakaryocytes and no well-formed capillaries, alongside partially duplicated retinas and small lenses. Definitive myeloerythroid lineages are present but colony-forming cell numbers are dramatically reduced, and mutant fetal liver cells fail to radioprotect lethally irradiated animals and compete poorly in repopulation assays 6.

Human constraint agrees: pLI ~1.0, LOEUF 0.207, 5 observed loss-of-function variants against 50.8 expected — a well-powered estimate of strong constraint 5.

An embryonic-lethal knockout with a megakaryocyte and vascular phenotype, plus a repopulation defect, is a difficult starting point for a drug in infants, where megakaryocyte output and marrow reconstitution are both already compromised by the disease and its treatment. The project's triage placed MEIS1 AMBER on LOEUF 0.207; the mouse phenotype argues for worse than AMBER.

Structurally, MEIS1 is 390 residues with a MEIS N-terminal domain at 108–192 7 and only two PDB entries, both DNA-bound heterodimers: 4XRS (MEIS1 with DLX3 on specific DNA, 3.50 Å) and 5EGO (HOXB13–MEIS1 on methylated DNA, 2.54 Å) 8. Both capture the interaction surface that the biology says matters, which is the one encouraging structural fact in this entry.

The epigenetics of MEIS1: a target locus, an acetyltransferase recruiter, and a substrate of a histone deubiquitinase

MEIS1 is a TALE-class homeodomain transcription factor with no methyltransferase, demethylase, acetyltransferase or deacetylase activity, so it writes and erases nothing. It is nonetheless wrong to record MEIS1 as epigenetically not-applicable, because it sits in three distinct relationships to chromatin, and they carry different amounts of evidence and different systems.

1. As a target locus, and the response is not a single-mark story. MEIS1 falls when H3K79 methylation is depleted, by DOT1L deletion or by high-concentration pinometostat. The informative part is what the calibrated measurement shows: by ICeChIP-seq, H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion target genes with paradoxical increases of H3K4me3 and loss of H3K27me3 E9. An entry that recorded only "H3K79me2 at MEIS1" would therefore be recording the smallest true part of a three-mark response. Cause versus consequence at this locus is as unresolved as at HOXA9, for the same reason: H3K79me2 is deposited co-transcriptionally.

2. As a recruiter of an acetyltransferase — the part this graph had nowhere. Hoxa9 and Meis1 co-bind hundreds of highly evolutionarily conserved sites, most of them distant from transcription start sites, and those sites carry high H3K4me1 and CBP/p300 binding, the signature of enhancers; a subset shows enhancer activity in transient transfection. Conditional Hoxa9 activation is associated with CBP/p300 recruitment, histone acetylation and transcriptional activation of a proto-oncogene network including Erg, Flt3, Lmo2, Myb and Sox4 E10. So the HOXA9/MEIS1 module's mechanism of action is, in part, the recruitment of a histone acetyltransferase to distal elements. Two cautions travel with it: the system is murine haematopoietic cells with conditional Hoxa9, not a KMT2A-fusion cell, and the acetylation is attributed to Hoxa9 activation, with MEIS1 established as a co-binder rather than as the recruiting moiety.

3. As a non-histone substrate of a histone deubiquitinase. A genome-wide CRISPR screen in a KMT2A-rearranged B-ALL line identified USP22 as the regulator of MEIS1 protein stability: genetic or chemical USP22 inhibition polyubiquitinates MEIS1 and sends it to the proteasome, and ChIP shows cooperative USP22 and MEIS1 binding at oncogenic target genes E11. What makes this epigenetic rather than merely proteostatic is what USP22 normally is — the catalytic subunit of the ATXN7L3/USP22/ENY2 module of the GCN5-containing TFTC/STAGA (SAGA) complex, which carries histone H2A and H2B deubiquitinase activity and, in Drosophila, enhances position-effect variegation E12. MEIS1 is therefore a non-histone substrate of an enzyme whose canonical substrates are H2A and H2B ubiquitin, in a complex that also acetylates histones. This is the only one of the three connections demonstrated in the right disease.

What is not here. There is no bivalency record for MEIS1 and this tranche did not create one: MEIS1[tiab] AND bivalent[tiab] returns a single record and it is about a bivalent NR2F1 gene under retinoic acid, not about MEIS1's locus. The same query shape returns 17 for H3K79 and 5 for H3K27me3, so the instrument demonstrably returns ones. This is consistent with, and does not close, the standing absence in cell-state-primed-bivalent-chromatin. And PDB 5EGO, already listed in this entry, turns out to be a HOXB13-MEIS1 heterodimer bound to methylated DNA at 2.54 Å, deposited from the methyl-SELEX survey of 542 human transcription factors that found many mCpG-preferring factors concentrated in the extended homeodomain family, with methylcytosine specificity arising from direct hydrophobic contacts to the 5-methyl group E13. Whether MEIS1's own TALE homeodomain makes such a contact — as opposed to HOXB13, the factor that study highlights — is not established from what was read here, and is recorded as an open question rather than as a 5mC-reader claim.

Facts and figures
uniprotO00470
gene symbolMEIS1
ensemblENSG00000143995
length AA390
alphafold IDAF-O00470-F1
cytoband2p14
roleTALE-class HOXA9 cofactor; rate-limiting regulator of MLL leukemia stem cell potential. Output programme, not a fusion-complex subunit.
functional unitMEIS1-PBX interaction; the Meis1 requirement runs through redundant Pbx2 and Pbx3
druggabilityPoor for MEIS1 itself: a TALE homeodomain transcription factor with two low-to-moderate-resolution DNA-bound structures and no PBX-containing structure. The MEIS1-PBX interface is the biologically indicated target and has no structure in this protein's PDB set.
subnuclear localizationunpublished - no subnuclear observation of MEIS1 exists in any system, despite its partner HOXA9 having named nuclear bodies
shown for fusionNO - MEIS1 protein has never been localised in a KMT2A-rearranged cell, although it is one of the canonical fusion target genes
epigenetic readoutNOT A CHROMATIN ENZYME, BUT NOT 'NOT APPLICABLE' EITHER - MEIS1 has three separate epigenetic connections and none of them is a mark it writes. (1) TARGET LOCUS: MEIS1 is downregulated when H3K79 methylation is depleted by DOT1L deletion or high-dose pinometostat, and by calibrated ICeChIP-seq H3K79me2 is markedly depleted at MLL-fusion targets with PARADOXICAL INCREASES of H3K4me3 and LOSS of H3K27me3 - so the chromatin response at fusion targets is not a simple one-mark story. (2) RECRUITER OF AN ACETYLTRANSFERASE, not a writer: Hoxa9 and Meis1 co-bind hundreds of highly conserved, mostly TSS-distal sites carrying high H3K4me1 and CBP/p300 - an enhancer signature - and conditional Hoxa9 activation drives CBP/p300 recruitment and histone acetylation at a proto-oncogene network including Erg, Flt3, Lmo2, Myb and Sox4 (murine haematopoietic cells, NOT a KMT2A-fusion system). (3) A HISTONE DEUBIQUITINASE ACTS ON MEIS1 AS A NON-HISTONE SUBSTRATE: USP22, the catalytic subunit of the ATXN7L3/USP22/ENY2 H2A and H2B deubiquitination module of SAGA/TFTC-STAGA, protects MEIS1 protein from polyubiquitination and proteasomal degradation, and USP22 and MEIS1 co-bind oncogenic target genes by ChIP in KMT2A-rearranged B-ALL - the only one of the three shown in the right disease, though the partner is not stated as KMT2A::AFF1. 5mC: PDB 5EGO is a HOXB13-MEIS1 heterodimer on METHYLATED DNA, from the methyl-SELEX survey that found the extended homeodomain family enriched for mCpG-PREFERRING factors; whether MEIS1's own TALE homeodomain contacts the 5-methyl group is UNRESOLVED here and must not be asserted. BIVALENCY: bounded absence - MEIS1[tiab] AND bivalent[tiab] returns 1 record and it is off-topic (a bivalent NR2F1 gene), while the identical query shape returns 17 for H3K79 and 5 for H3K27me3, so the instrument returns ones. CAUSE OR CONSEQUENCE at the MEIS1 locus: UNRESOLVED, same as HOXA9.
PDB IDS
[
  "4XRS",
  "5EGO"
]
PDB verified
[
  "4XRS",
  "5EGO"
]
domains
[
  {
    "name": "MEIS N-terminal domain",
    "start": 108,
    "end": 192,
    "pfam": null
  }
]
essentiality
{
  "depmap_common_essential": false,
  "chronos_mean": -0.053,
  "chronos_mean_leukemia_lines": -0.0896,
  "n_lines": 1258,
  "fraction_lines_depleted": 0.0132,
  "gnomad_pLI": 1,
  "gnomad_loeuf": 0.2071,
  "gnomad_obs_lof": 5,
  "gnomad_exp_lof": 50.8,
  "mouse_ko": "Embryonic lethal by E14.5: extensive haemorrhage, absent megakaryocytes, no well-formed capillaries, duplicated retinas and small lenses; fetal liver cells fail to radioprotect and compete poorly in repopulation",
  "hpa_ntpm": {
    "spleen": 16.8,
    "heart_muscle": 12.3,
    "thymus": 4.4,
    "liver": 3.5,
    "testis": 2.7,
    "bone_marrow": 2.4,
    "lymph_node": 2.2,
    "classical_monocyte": 0,
    "naive_B_cell": 0
  },
  "hpa_specificity": "Low tissue specificity"
}
codependency men1
{
  "r_all_lines": 0.0771,
  "r_leukemia_lines": 0.468,
  "ci_leukemia": [
    0.198,
    0.691
  ],
  "p_permutation": 0.0004,
  "p_holm": 0.008,
  "survives_holm": true,
  "rank_among_survivors": 7,
  "n_leukemia_lines": 54
}
post translational regulation
{
  "regulator": "USP22 (SAGA deubiquitinase)",
  "mechanism": "protects MEIS1 from polyubiquitination and proteasomal degradation",
  "source_pmid": "42418681",
  "found_in": "genome-wide CRISPR/Cas9 screen, KMT2A-rearranged B-ALL cell line",
  "note": "Relevant to why MEIS1 reads as unresolved across transcript- and dependency-based designs in this project: those designs cannot see a protein-stability mechanism."
}
localization
{
  "subcellular": "The human annotation is NOT a measurement: UniProt O00470 gives Nucleus with ECO:0000255|PROSITE-ProRule:PRU00108, a match to the homeodomain sequence model used in automatic assertion, and carries no experimental localisation evidence. Measured behaviour is isoform-dependent: mouse MEIS1-FL (homeodomain-containing) is nuclear and MEIS1-HdL (homeodomain-less) is CYTOPLASMIC, and the two are functionally antagonistic (PMID 42441717). Nuclear Meis1 is also stage-selective in vivo - dermal papilla, anagen phase only (PMID 31543346).",
  "subnuclear": "unpublished - no subnuclear observation of MEIS1 exists in any system read for this beat",
  "how_shown": "long-read cDNA sequencing with in vivo electroporation and isoform-resolved imaging (mouse cerebellum); immunohistochemistry on tissue sections (hair follicle, genital tract); no experimental localisation behind the human database annotation",
  "systems": "mouse cerebellar granule-cell progenitors, mouse vibrissa follicle, developing female genital tract; nothing haematopoietic and nothing leukaemic",
  "partner_inference_warning": "PBX1 is mostly cytoplasmic in epithelial endometrial cells despite nuclear MEIS1 (PMID 16172981), so nuclear MEIS1 does not entail a nuclear HOX/PBX/MEIS trimer",
  "node": "localization-meis1-nucleus-is-a-sequence-prediction-and-one-isoform-is-cytoplasmic"
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.4289,
  "chronos_mean_other_leukaemia": -0.1232,
  "difference": -0.3056,
  "pan_essentiality_all_lines": -0.053,
  "selectivity_rank": 84,
  "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."
}
epigenetic bounded absence
{
  "claim": "No bivalent-chromatin (H3K4me3/H3K27me3) measurement at the MEIS1 locus exists in the title/abstract index.",
  "date_measured": "2026-09-21",
  "tool": "NCBI esearch (eutils), querytranslation read back from the response",
  "queries": [
    {
      "query": "MEIS1[tiab] AND bivalent[tiab]",
      "querytranslation": "\"MEIS1\"[Title/Abstract] AND \"bivalent\"[Title/Abstract]",
      "count": 1,
      "title_checked": "the single hit is PMID 23666625, 'Polycomb recruitment attenuates retinoic acid-induced transcription of the bivalent NR2F1 gene' - off topic; 0 on topic"
    },
    {
      "query": "MEIS1[tiab] AND H3K79[tiab]",
      "querytranslation": "\"MEIS1\"[Title/Abstract] AND \"H3K79\"[Title/Abstract]",
      "count": 17,
      "role": "positive control through the IDENTICAL query shape - the instrument returns ones"
    },
    {
      "query": "MEIS1[tiab] AND H3K27me3[tiab]",
      "querytranslation": "\"MEIS1\"[Title/Abstract] AND \"H3K27me3\"[Title/Abstract]",
      "count": 5,
      "role": "second positive control, same shape"
    }
  ],
  "absence_class": "never-measured",
  "absence_class_basis": "Bounded by titles and abstracts only; supporting figures not searched (rule 80), and no GEO query was run for a bivalency-resolved dataset at this locus, so the class could fall to measured-not-analysed if deposited H3K4me3/H3K27me3 pairs in KMT2A-rearranged cells were re-analysed at MEIS1. Stated as never-measured because no primary bivalency demonstration in KMT2A-rearranged leukaemia exists anywhere in this corpus either - see cell-state-primed-bivalent-chromatin, which records the same gap at the level of the cell state.",
  "token_trap_found": "'bivalent' is a contaminated search token in THIS project's territory specifically: HOXA9[tiab] AND bivalent[tiab] returns 2 records and one of them (PMID 22936661) is about the BIVALENT MENIN-MLL protein-protein INTERACTION - two binding motifs - not about bivalent chromatin. A beat searching bivalency around the menin interface will retrieve interface papers and may read them as chromatin-state papers."
}
How this could bite us back
  • Developmental toxicity: Meis1-null embryos die at E14.5 with absent megakaryocytes and failed capillary formation. Megakaryocyte output and vascular integrity are both already fragile in an infant with hyperleukocytosis and thrombocytopenia.
  • Stem-cell toxicity: Meis1-null fetal liver cells fail to radioprotect and compete poorly in repopulation, which is the wrong property in a disease routinely treated with transplantation.
  • Redundancy at the partner: the requirement runs through redundant Pbx2 and Pbx3, so targeting one partner may be buffered.
  • Not orthogonal: MEIS1 falls when HOXA9 falls, and both fall downstream of the tether. A menin plus MEIS1 combination would be two hits on one axis.
  • Chemical USP22 inhibition is presented as a route to MEIS1 degradation, but USP22 is the catalytic subunit of a SAGA module whose normal job is removing H2A and H2B ubiquitin genome-wide. An inhibitor that works by destabilising one transcription factor would also perturb a global chromatin mark, so the on-target toxicity to consider is a chromatin-wide one and not a MEIS1-specific one.
Still open
  1. Is the MEIS1-MEN1 co-dependency a shared requirement or shared expression? MEIS1 is depleted in only 1.3% of lines, so the correlation may be measuring which lines turn MEIS1 on. Restricting the correlation to MEIS1-expressing lines would separate the two.
  2. Is there a structure of MEIS1 bound to PBX? The leukemia biology points at that interface and the two existing MEIS1 structures contain DLX3 and HOXB13 instead.
  3. Does the embryonic megakaryocyte and vascular phenotype have a postnatal counterpart? An inducible adult Meis1 deletion would tell this project whether the lethality is developmental-only, and that single fact decides whether MEIS1 is triage AMBER or RED.
  4. Since HOXA9 knockdown co-downregulates MEIS1, how much of the HOXA9 maintenance requirement is actually a MEIS1 requirement? A MEIS1 rescue in HOXA9-depleted cells would answer it.
  5. Does MEIS1's own TALE homeodomain contact 5-methylcytosine? PDB 5EGO is a HOXB13-MEIS1 heterodimer on methylated DNA, but the methyl-SELEX study it came from attributes mCpG preference to the homeodomain family and to HOXB13; nothing read here resolves which chain makes the hydrophobic contact to the 5-methyl group. An mCpG-preferring MEIS1 would point at the opposite chromatin compartment from the fusion's own unmethylated-CpG CXXC reader, which makes the question worth settling rather than assuming.
  6. Is USP22's requirement in KMT2A-rearranged leukaemia a MEIS1-stability requirement or an H2Bub-turnover requirement? The screen cannot separate them, USP22's canonical substrates are H2A and H2B ubiquitin, and this graph already holds the direction and selectivity of the H2Bub requirement in KMT2A leukaemia as unresolved. A catalytically dead USP22 rescue, or a MEIS1 stabilisation that bypasses USP22, would decide it.
  7. Does the HOXA9/MEIS1 enhancer module recruit CBP/p300 in a KMT2A-fusion cell? The co-binding, H3K4me1 and CBP/p300 result is murine and not fusion-driven, and it is the mechanism by which the fusion's best-known output could act on chromatin - so its absence from any KMT2A-rearranged system is a conspicuous gap rather than a detail.
Every source behind this entry (14)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential, required for induction and maintenance of MLL transformation, quantitatively setting LSC frequency via self-renewal, differentiation arrest and cycling, with the requirement running through redundant Pbx2 and Pbx3.

    Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. · Wong P, Iwasaki M, Somervaille TCP, So CWE, Cleary ML · Genes & Development 2007
    PMID 17942707DOI
    What this evidence cannot show

    Mouse MLL-fusion models, predominantly myeloid; not KMT2A::AFF1 infant B-ALL. Because the requirement is mediated through redundant Pbx proteins, MEIS1 alone may not be the correct pharmacological unit.

    Evidence that argues against this (1)
    • The self-renewal function Meis1 supplies to the leukemia stem cell is the same one it supplies to the normal haematopoietic stem cell, so 'rate-limiting for LSC potential' does not imply a therapeutic window. Conditional Meis1 knockout in ADULT mouse haematopoiesis significantly reduces HSPC numbers through impaired self-renewal and reduced quiescence, cell-autonomously, producing stem-cell exhaustion and defective long-term haematopoiesis, and it downregulates a subset of Pbx1-dependent HSC signature genes. This is the adult phenotype, not the embryonic lethality already noted in E6, and it is the one that matters for a drug given to a child who needs marrow recovery. It is also mechanistically the same axis: E1 says the MLL requirement runs through Pbx2/Pbx3, and the normal-HSC requirement runs through the Pbx1 programme. Ariki R et al. 2014
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Molecular dissection of Meis1 identifies two domains required for leukemia induction, the PBX-interaction motif and a C-terminal transactivation domain, with a key role for Hoxa gene activation.

    Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation. · Mamo A, Krosl J, Kroon E, Bijl J, Thompson A, Mayotte N, Girard S, Bijl J, Rosten P, Humphries K, Sauvageau G · Blood 2006
    PMID 16469876DOI
    What this evidence cannot show

    Structure-function work in mouse retroviral leukemia models; domain requirements for induction may differ from those for maintenance of established human disease.

    Evidence that argues against this (1)
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    HOXA9 suppression in MLL-rearranged human leukemia cells co-downregulates MEIS1 alongside HOXA10, PBX3 and MEF2C, so MEIS1 is not an independent node from HOXA9.

    HOXA9 is required for survival in human MLL-rearranged acute leukemias. · Faber J, Krivtsov AV, Stubbs MC, Wright R, Davis TN, van den Heuvel-Eibrink M, Zwaan CM, Kung AL, Armstrong SA · Blood 2009
    PMID 19056693DOI
    What this evidence cannot show

    RNA interference in cell lines; co-downregulation establishes circuit membership, not the direction of causation between HOXA9 and MEIS1.

    Evidence that argues against this (1)
    • If MEIS1 is co-downregulated with HOXA10, PBX3 and MEF2C on HOXA9 suppression, then MEIS1 is not an independent node, and the entry says so. That undercuts MEIS1 as a separate target and the dossier should carry the consequence. Oncofusion knowledge graph (internal analysis) 2026
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    Across 54 DepMap leukemia lines MEIS1 correlates with MEN1 at r = 0.468 (95% CI 0.198-0.691, permutation p = 0.0004, Holm p = 0.008), surviving multiple-testing correction and ranking seventh of ten survivors.

    DepMap co-dependency with MEN1, leukemia-restricted, with bootstrap confidence intervals and permutation testing; analyses/depmap-bootstrap-ci/ in this project · Broad Institute DepMap; Open Targets Platform; analysis run by this project · Database and derived analysis 2026
    What this evidence cannot show

    Our own computation in 54 lines with a wide interval. MEIS1 is expressed in few lines and depleted in only 1.3% of them, so the correlation may be tracking which lines express MEIS1 rather than a shared requirement. Surviving Holm correction rules out noise, not confounding.

    Evidence that argues against this (1)
    • This project's own deeper null overturns the number reported here. Re-run against a 2,743-gene variance-matched null with Holm correction (ana-depmap-null-deep-pool, this cycle), MEIS1 does NOT survive correction: Holm p = 0.067, against MEF2C and KAT7 which do. The r = 0.468 / Holm 0.008 figure in this evidence item came from a 16-gene panel whose correction was against a criterion since shown to be unstable, and two earlier versions of the analysis reached different conclusions. The MEIS1 co-dependency should be read as a near-miss, not a survivor. All of this is our own unreviewed computation on 54 leukemia lines with an uncontrolled lineage confounder and does not carry the weight of E1's mouse genetics either way. Broad Institute DepMap; Open Targets Platform; analysis run by this project 2026
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    MEIS1 is not DepMap common-essential (mean Chronos -0.053 across 1,258 lines, -0.090 across leukemia lines, 1.3% of lines depleted) and is strongly constrained in humans (pLI ~1.0, LOEUF 0.207, 5 observed against 50.8 expected loss-of-function variants); HPA reports spleen 16.8 and bone marrow 2.4 nTPM.

    What this evidence cannot show

    DepMap release version not stated by the API. A shallow dependency in a gene expressed in few lines is uninformative about its importance where it is expressed.

    Evidence that argues against this (1)
    • The 'not DepMap common-essential' line materially understates the safety liability, and a published adult conditional knockout shows why. Cell lines in culture are not under reconstitution stress; adult Meis1 deletion in vivo causes impaired HSPC self-renewal, loss of quiescence and stem-cell exhaustion with defective long-term haematopoiesis. A gene effect of -0.053 across 1,258 proliferating lines is a poor proxy for what happens to a stressed stem-cell compartment, and the LOEUF of 0.207 and pLI ~1.0 reported in the same evidence item are the discordant signal that should be believed. Ariki R et al. 2014
  6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Meis1-deficient mouse embryos die by embryonic day 14.5 with extensive haemorrhage, absent megakaryocytes and no well-formed capillaries, plus partially duplicated retinas and small lenses; definitive myeloerythroid lineages are present but colony-forming cell numbers are dramatically reduced, and mutant fetal liver cells fail to radioprotect lethally irradiated animals and compete poorly in repopulation assays.

    Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. · Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, Devor-Henneman DE, Saiki Y, Kutsuna H, Tessarollo L, Jenkins NA, Copeland NG · EMBO Journal 2004
    PMID 14713950DOI
    What this evidence cannot show

    Germline knockout from conception; embryonic lethality reflects a developmental requirement, particularly in vasculature and megakaryopoiesis, and does not directly predict the effect of partial postnatal pharmacological inhibition. It does establish that the affected compartments include ones that matter in an infant with leukemia.

    Evidence that argues against this (1)
    • This is a mouse knockout describing what the gene does in normal development or normal haematopoiesis, over the animal's whole life, with the protein entirely absent. A drug gives partial reversible inhibition in an adult for weeks. The experiment bounds the biological requirement and not the therapeutic window. Embryonic lethality at E14.5 with absent megakaryocytes and vascular failure describes a developmental requirement and gives no information about an adult on a drug. Nature 2012
  7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProt O00470 annotates human MEIS1 as 390 residues with a MEIS N-terminal domain at 108-192.

    What this evidence cannot show

    The TALE homeodomain and the C-terminal transactivation domain identified as functionally required are not separately annotated as features in this record; their coordinates should be read from the primary structure-function work.

    Evidence that argues against this (1)
    • One annotated domain in 390 residues is a UniProt curation, and the unannotated remainder is where the transactivation function the entry's own E2 identifies must sit. UniProt Consortium 2026
  8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Only two PDB entries cover MEIS1, both DNA-bound heterodimers: 4XRS (MEIS1 with DLX3 on specific DNA, 3.50 A) and 5EGO (HOXB13-MEIS1 on methylated DNA, 2.54 A).

    What this evidence cannot show

    Neither structure contains PBX, which is the partner the leukemia biology implicates; and 4XRS at 3.50 A is too low in resolution for side-chain-level interface design.

    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. Both entries are DNA-bound heterodimers with partners (DLX3, HOXB13) that are not the ones MEIS1 acts through in this disease, so neither shows the surface a PBX-interaction-directed agent would target. RCSB PDB 2026
  9. E_usp22_protein_stabilitystrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MEIS1 is controlled at the level of PROTEIN STABILITY, not only transcription. A genome-wide CRISPR/Cas9 screen in a KMT2A-rearranged B-ALL line identified the deubiquitinase USP22, a SAGA complex member, as a regulator of MEIS1 protein abundance. USP22 and MEIS1 bind cooperatively at oncogenic target genes, and genetic or chemical inhibition of USP22 causes MEIS1 polyubiquitination, proteasomal degradation and loss of target-gene expression. USP22 depletion impairs growth in KMT2A-rearranged models.

    USP22 is a novel vulnerability regulating MEIS1 protein abundance and gene transcription in KMT2Ar acute leukemia · Bröchtel S, Schneider C, Müller M, et al. · Blood, online ahead of print 8 July 2026 2026
    PMID 42418681DOI
    What this evidence cannot show

    Read as abstract only; online ahead of print. The screen was run in one KMT2A-rearranged B-ALL cell line, and the growth effect is reported for 'KMT2Ar acute leukemia models' without the abstract specifying how many or which. 'Chemical inhibition' is stated but the compound, its selectivity and whether the effect is on-target are not established from the abstract. No infant-derived material is mentioned.

    Evidence that argues against this (1)
    • This does not resolve MEIS1's standing as a target so much as relocate the problem. If MEIS1 abundance is set post-translationally, then transcript-level and CRISPR dependency measures are both indirect readouts of it, which is a plausible reason MEIS1 has come out unresolved across this project's DepMap designs - but it equally means the druggable node is USP22, not MEIS1, and USP22 is a SAGA deubiquitinase with broad substrates. Degrading MEIS1 by removing its deubiquitinase is a mechanism with obvious scope for collateral effects, and the abstract reports no selectivity data. Bröchtel S et al. 2026
  10. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MEIS1 is a target-locus readout rather than a chromatin enzyme: depletion of H3K79 methylation by DOT1L deletion or high-concentration pinometostat downregulates HOXA9 and MEIS1, and by calibrated internal-standard ICeChIP-seq H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion target genes with paradoxical increases of H3K4me3 and loss of H3K27me3.

    PMID 34263728DOI
    What this evidence cannot show

    Abstract read from the eutils record; full text not read in this tranche, and this graph already carries the paper's low-dose FLT3 mechanism in mechanism-h3k79me2-noncanonical-flt3-survival, so this item is recorded for the three-mark chromatin response rather than to restate that. The fusion partner is 'MLL-rearranged' and is not stated as KMT2A::AFF1 in the abstract; the system is a leukaemia cell line panel, not infant B-lineage primary material. The H3K4me3 and H3K27me3 changes are reported at MLL-fusion targets as a class, not resolved to the MEIS1 locus, so 'H3K4me3 rises at MEIS1' would overstate it.

    Evidence that argues against this (1)
    • Downregulation of MEIS1 on H3K79 depletion does not establish that H3K79me2 at the MEIS1 locus is what sustains it. In an inducible MLL-ENL (KMT2A::MLLT1) system, fusion binding and H3K79 methylation changes are confined to part of the genome and only 12 of 223 fusion-bound genes are significantly upregulated on induction; Meis1 is one of them, but the same counts show that the mark's presence at a bound locus is usually insufficient for activation. The mark could equally be a readout of the transcription it accompanies. Wang QF et al. 2011
  11. E10moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Hoxa9 and Meis1 co-bind hundreds of highly evolutionarily conserved sites, most distant from transcription start sites, which carry high H3K4 monomethylation and CBP/P300 binding characteristic of enhancers and a subset of which show enhancer activity in transient transfection; conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a proto-oncogene network including Erg, Flt3, Lmo2, Myb and Sox4.

    Identification and characterization of Hoxa9 binding sites in hematopoietic cells. · Huang Y, Sitwala K, Bronstein J, et al. · Blood 2012
    PMID 22072553DOI
    What this evidence cannot show

    Abstract read from the eutils record; full text not read. MURINE haematopoietic cells with conditional Hoxa9, NOT a KMT2A-rearranged system and not human - so this establishes the HOXA9/MEIS1 module's enhancer mechanism in normal/immortalised murine haematopoiesis and is imported to the fusion context only by analogy. The acetylation and CBP/p300 recruitment are attributed to Hoxa9 activation; MEIS1 is established as a genome-wide co-binder at those elements, not as the recruiting moiety, so MEIS1 must not be written as a p300 recruiter on this evidence. H3K4me1 and CBP/p300 are co-occupancy profiles, not perturbation experiments.

    Evidence that argues against this (1)
    • The enhancer-signature reading assumes the module's targeting is sequence- and cofactor-driven. There is a rival, DNA-modification-driven possibility that the same data cannot exclude: methyl-SELEX over 542 human transcription factors found that many factors PREFER CpG-methylated sequences and that these are concentrated in the extended homeodomain family, to which both HOXA9 and MEIS1 belong. If MEIS1 or HOXA9 site selection is partly mCpG-directed, then 'distal conserved sites with H3K4me1' describes where they end up rather than why, and the causal arrow between the enhancer marks and the binding is not fixed by co-occupancy. Yin Y et al. 2017
  12. E11strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MEIS1 is a NON-HISTONE SUBSTRATE of a histone deubiquitinase: a genome-wide CRISPR/Cas9 screen in a KMT2A-rearranged B-ALL cell line identified USP22, a subunit of the SAGA complex, as a regulator of MEIS1 protein stability; genetic or chemical USP22 inhibition causes MEIS1 polyubiquitination and proteasomal degradation with downregulation of its expression programme, USP22 depletion impairs growth in KMT2A-rearranged models, and chromatin immunoprecipitation shows cooperative USP22 and MEIS1 binding at critical oncogenic target genes.

    PMID 42418681DOI
    What this evidence cannot show

    Abstract read from the eutils record; full text not read in this tranche. The cell context is KMT2A-rearranged B-ALL, which is the right disease, but the abstract does not name the 3' partner, so this is NOT established as KMT2A::AFF1 - rule 86 applies and the field should not be read as index-fusion evidence. 'Cooperative binding' from ChIP is co-occupancy, not a demonstrated joint requirement at those loci. Whether USP22's H2Bub deubiquitinase activity is involved at all in the MEIS1 effect is not addressed: the mechanism described is protection of a non-histone protein from the proteasome, and a deubiquitinase can do that without touching chromatin.

    Evidence that argues against this (1)
    • The chromatin framing must not be overread, and the founding characterisation of the module is why. USP22's established activity, with ATXN7L3 and ENY2 inside the GCN5-containing TFTC/STAGA complex, is histone H2A and H2B DEUBIQUITINATION - it removes a mark rather than depositing one, and the module acts as an enhancer of position-effect variegation and a coactivator for nuclear receptors. So an entry could equally read USP22's requirement in KMT2A-rearranged leukaemia as an H2Bub-turnover requirement rather than a MEIS1-stability requirement, and the two are not separated by the screen. This graph's own H2Bub entries already hold that the direction and selectivity of the H2Bub requirement in KMT2A leukaemia are unresolved. Zhao Y et al. 2008
  13. E12established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    The enzyme that stabilises MEIS1 is a histone deubiquitinase by trade: the 2 MDa GCN5 histone-acetyltransferase-containing metazoan TFTC/STAGA (SAGA) complexes carry a histone H2A and H2B deubiquitinase activity, and ATXN7L3, USP22 and ENY2 are the three subunits that form that deubiquitination module; the module is an enhancer of position-effect variegation in Drosophila and is required as a cofactor for full transcriptional activity by nuclear receptors.

    PMID 18206972DOI
    What this evidence cannot show

    Abstract read from the eutils record; full text not read. This is the founding characterisation of the module in HeLa-derived complexes and Drosophila, not in leukaemia, and it establishes what USP22 normally does rather than what it does to MEIS1. It is cited here only to fix the identity of the enzyme: nothing in it concerns MEIS1, KMT2A or leukaemia, and it must not be cited as evidence about the fusion.

    Evidence that argues against this (1)
    • The pairing of these two papers is where the interpretive risk sits, and it should be named rather than smoothed over. The KMT2A-rearranged screen describes USP22 acting on a NON-HISTONE substrate - protecting MEIS1 protein from the proteasome - which a deubiquitinase can do with no chromatin involvement at all. So the SAGA/H2Bub identity of USP22 does NOT license reading the MEIS1 result as a chromatin mechanism, and this entry records the two facts side by side precisely so that a later reader does not fuse them into 'USP22 deubiquitinates histones to stabilise MEIS1', which neither paper says. Bröchtel S et al. 2026
  14. E13moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    PDB 5EGO, one of only two structures covering MEIS1 and already listed in this entry, is a HOXB13-MEIS1 heterodimer bound to METHYLATED DNA at 2.54 A X-ray resolution, deposited from a methylation-sensitive SELEX survey of 542 human transcription factors which found many factors that prefer CpG-methylated sequences, concentrated in the extended homeodomain family, with homeodomain specificity for methylcytosine depending on direct hydrophobic interactions with the 5-methyl group.

    PMID 28473536DOI
    What this evidence cannot show

    Abstract read from the eutils record; the structure record was fetched live from the RCSB entry API on 2026-09-21, which returns the title 'HOXB13-MEIS1 heterodimer bound to methylated DNA', X-RAY DIFFRACTION and 2.54 A. CRITICAL LIMIT: this does NOT establish that MEIS1 reads 5mC. The mCpG preference in that work is a property attributed to homeodomain factors generally and to HOXB13 in particular, and nothing read here says which chain of 5EGO contacts the 5-methyl group. SELEX is in vitro naked DNA, so a methylation preference there is not a statement about occupancy in cells, where hypomethylated regulatory elements are the norm. MEIS1 is a TALE-class homeodomain, structurally distinct from the canonical homeodomains the study highlights.

    Evidence that argues against this (1)
    • Even if a mCpG preference were established for MEIS1, its relevance to this disease would be contested by the methylation landscape rather than supported by it. Promoter CpG island methylation separates MLL-rearranged infant ALL subtypes, with t(4;11) and t(11;19) extensively HYPERmethylated while t(9;11) and MLL-germline infant ALL resemble normal bone marrow - so 5mC in the index fusion's own subtype is a subtype-specific silencing landscape, and the index fusion's own reader, the retained KMT2A CXXC domain, binds UNmethylated CpG. A homeodomain that preferred methylated DNA would be pointing at the opposite chromatin compartment from the fusion that drives it, which is a reason to treat the 5EGO observation as a structural curiosity until a cellular test exists. Stumpel DJ et al. 2009
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