LEO1 — the weakest-evidenced entry in the PAF1 complex, and the gene whose Ensembl id this project already got wrong once
also called LEO1 · RNA polymerase-associated protein LEO1 · LEO1 homolog
LEO1 is the fourth protein in the PAF1 machine. Unlike the other three it has never been studied on its own in KMT2A-fusion leukemia, and it is also the gene where this project once pulled data for the wrong gene entirely because of a bad identifier.
The same thing, for a scientist
LEO1 (Q8WVC0, 666 aa) is a constitutive PAF1C subunit with no primary study testing it individually in KMT2A-fusion leukemia. Unlike the other PAF1C subunits it is not DepMap common-essential (mean Chronos -0.213, only 7.7% of lines depleted), and it shows a nominal leukemia-restricted correlation with MEN1 of r = 0.302 that fails Holm correction. That combination -- intermediate essentiality plus a nominal correlation -- makes it the one PAF1C subunit worth a second look, on evidence that is currently too thin to act on.
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.
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.
Correction: 'constitutive subunit' is withdrawn
This entry described LEO1 as a constitutive subunit of PAF1C while a counter-evidence item in the same file recorded that the description overstates its integration — in fission yeast Leo1-Paf1 behaves as a separable sub-complex, dispensable for viability and antagonistic to silencing.
The wording is withdrawn. The accurate statement is that LEO1 is annotated as a core PAF1C subunit and is not constitutively integrated across species, and that the MLL contact is not mapped to LEO1 specifically.
This sits alongside a related finding in gene-rtf1: human RTF1 is reported not stably associated with PAF1C outside S. cerevisiae. Two of the complex's named subunits are therefore less firmly part of it than the phrase 'PAF1 complex' implies, which matters because this graph has treated PAF1C as a unit when reasoning about whether it is a second druggable handle on the retained fragment.
The identifier warning attached to this gene
This project's cycle-8 co-dependency run silently returned data for the wrong gene because the Ensembl identifier used for LEO1 actually resolves to ITPRID2. It was caught only because the script reported which requested symbols came back empty and an unexpected symbol appeared in the output. The corrected id is ENSG00000166477, which is the id used for every figure in this entry, and the corrected value put LEO1 at r = 0.09 on the full panel.
That episode is why this entry states its identifiers explicitly and why every accession quoted here was fetched rather than recalled. Any future agent reading this node should treat a LEO1 number from an uncited source as suspect.
LEO1 does not behave like the rest of PAF1C
PAF1, CTR9 and CDC73 are all DepMap common-essential, depleted in 93%, 93% and 99% of lines respectively. LEO1 is not: mean Chronos -0.213, depleted in only 7.7% of 1,258 lines, and not flagged common-essential 3.
That is a genuine asymmetry within an obligate-looking complex, and it is the same shape of observation as DPY30 within WRAD. It says that LEO1 is either dispensable for the complex's essential function, or redundant, or that PAF1C tolerates its loss in most contexts.
In the leukemia-restricted run LEO1 comes out at r = 0.302 (95% CI 0.049–0.539, permutation p = 0.026) — nominally non-zero, comfortably failing Holm correction across 16 genes 4. On its own that is nothing. Taken with the essentiality asymmetry it is the kind of loose thread that occasionally turns into something, and it costs little to record.
What is not known
No primary study tests LEO1 individually in KMT2A-fusion leukemia 2. Its membership of the fusion-associated interactome rests entirely on PAF1C complex purifications 1. There is no verified mouse knockout. UniProt annotates no domain in the 666-residue sequence, and LEO1 is resolved only within Pol II elongation-complex cryo-EM maps 5.
The honest classification is complex-inferred, subunit-unvalidated, the same as CTR9, with the additional observation that LEO1's essentiality profile does not match its complex-mates.
| uniprot | Q8WVC0 |
|---|---|
| gene symbol | LEO1 |
| ensembl | ENSG00000166477 |
| ensembl warning | An earlier run in this project used an identifier that resolved to ITPRID2 and silently produced data for the wrong gene. Always verify. |
| length AA | 666 |
| alphafold ID | AF-Q8WVC0-F1 |
| complex | PAF1C (PAF1, CTR9, LEO1, CDC73, WDR61) |
| evidence class | complex-inferred, subunit-unvalidated |
| druggability | Unassessed and unpromising: largely disordered, no isolated structure, no annotated domain, no subunit-level validation. |
PDB verified
[ "6TED", "7OPC", "8A3Y" ]
domains
[]
essentiality
{
"depmap_common_essential": false,
"chronos_mean": -0.2126,
"chronos_mean_leukemia_lines": -0.2257,
"n_lines": 1258,
"fraction_lines_depleted": 0.077,
"gnomad_pLI": 0.0966,
"gnomad_loeuf": 0.5628,
"gnomad_obs_lof": 34,
"gnomad_exp_lof": 80.4,
"mouse_ko": "Not established; no Leo1 knockout citation verified and none asserted",
"hpa_ntpm": {
"liver": 20.8,
"thymus": 20.6,
"lymph_node": 16.8,
"naive_B_cell": 16.5,
"classical_monocyte": 14.5,
"spleen": 9.9,
"testis": 8.7,
"bone_marrow": 8.4
},
"hpa_specificity": "Low tissue specificity"
}codependency men1
{
"r_leukemia_lines": 0.3016,
"ci_leukemia": [
0.0487,
0.5388
],
"crosses_zero": false,
"p_permutation": 0.02599,
"p_holm": 0.28589,
"survives_holm": false
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.4199,
"chronos_mean_other_leukaemia": -0.2521,
"difference": -0.1678,
"pan_essentiality_all_lines": -0.2126,
"selectivity_rank": 367,
"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."
}- Evidence risk: LEO1 is carried in KMT2A interactome lists on complex membership alone. Anything built on a direct LEO1-fusion contact is building on nothing.
- Identifier risk: this gene has already caused one silent wrong-gene analysis in this project. Any LEO1 figure not traceable to ENSG00000166477 should be discarded.
- Why is LEO1 the only PAF1C subunit that is not pan-essential? Either it is dispensable for PAF1C's essential function or the complex tolerates its loss, and both would change how the complex is drawn in this graph.
- Does LEO1's nominal leukemia correlation with MEN1 survive in a larger leukemia panel? It is the only PAF1C subunit with any signal at all, and the only one with the variance needed to produce one.
- Is LEO1 required for the MLL-PAFc interaction specifically, as opposed to for PAF1C assembly generally? Nobody has asked.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
LEO1 is a core-annotated subunit of the PAF1 complex, though its integration is not constitutive across species, which binds MLL via CxxC-flanking sequences and synergises with MLL fusion proteins at HOX loci.
The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. · Muntean AG, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly JA, Basrur V, Elenitoba-Johnson KSJ, Hess JL · Cancer Cell 2010What this evidence cannot show
Complex-level evidence only; LEO1 is not individually tested in this paper and the MLL contact is not mapped to a subunit. **The fusion is MLL-AF9 and the leukaemogenesis assay is murine**, neither of which this item previously stated: the abstract's functional claims are PAFc augmentation of MLL-AF9-mediated transcriptional activation of *Hoxa9* (murine nomenclature) and abolition of MLL-AF9-mediated immortalisation. AF9 is not a partner of KMT2A::AFF1, so the synergy-at-HOX-loci half of this claim reaches the index fusion only by import across fusion and species. The sibling entry `gene-rtf1`, drawing on the same paper, already said so; this one did not. Flagged by the partner-provenance audit as the single unflagged import in a 48-item stratified sample, and confirmed by the coordinator against the efetch abstract on 2026-09-19.
Evidence that argues against this (2)
- 'Constitutive subunit' overstates LEO1's integration into PAF1C, and its independent function partly opposes the activating role assumed here. In fission yeast, Leo1-Paf1 behaves as a separable subcomplex whose job is to PREVENT heterochromatin spreading into euchromatin: loss of Leo1 increases heterochromatin stability at facultative heterochromatin loci in an RNAi-independent manner, and deleting leo1 decreases nucleosome turnover. The cells are viable. A subunit that is dispensable for viability, separable from the complex core and antagonistic to silencing is not straightforwardly 'a constitutive subunit of the complex that synergises with MLL fusions at HOX loci'. Caveat: fission yeast, not human leukemia, so this bounds the inference rather than refuting it. Sadeghi L et al. 2015
- The binding half and the leukaemia half of this claim have different reach. MLL binding PAFc through CxxC-flanking sequences is a property of the KMT2A N-terminus, which every translocation retains, so it transfers to KMT2A::AFF1 by the same argument that carries the menin interface. The synergy and immortalisation results are MLL-AF9-specific and murine and do not. An entry that states both in one sentence invites the reader to carry the weaker one as far as the stronger. Cancer Cell 2010
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
A targeted literature search returned no primary study testing LEO1 individually in KMT2A-fusion leukemia, making LEO1 the weakest-evidenced member of the PAF1 complex in this interactome.
PubMed search for LEO1 in the context of KMT2A/MLL-fusion leukemia, conducted for this graph on 2026-09-18; no primary subunit-level study retrieved · Oncofusion Knowledge Graph project, using the NCBI PubMed E-utilities · Literature search 2026What this evidence cannot show
A negative search is bounded by query terms and indexing and is not proof that no such study exists.
Evidence that argues against this (1)
- The gap is real but it is not simply an untested gene: Leo1 has been studied directly, just outside leukemia, and what that work shows argues against the assumption that testing LEO1 in KMT2A-fusion leukemia would find an activating role. In fission yeast Leo1 acts to prevent heterochromatin spreading and to promote nucleosome turnover, and leo1 deletion stabilises heterochromatin and silences genes rather than de-repressing them; leo1 cells are viable and die only after prolonged nitrogen starvation. Combined with LEO1's mild DepMap profile (7.7% of lines depleted, pLI 0.097), the prior for LEO1 being a required activating subunit of a leukemogenic PAFc is low, and the entry should say so rather than leaving the gap neutral. Oya E et al. 2019
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
Unlike PAF1, CTR9 and CDC73, LEO1 is not DepMap common-essential: mean Chronos -0.213 across 1,258 lines with only 7.7% of lines depleted; gnomAD reports pLI 0.097 and LOEUF 0.563 with 34 observed against 80.4 expected loss-of-function variants.
DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API; gnomAD v4 constraint via the gnomAD GraphQL API; Human Protein Atlas consensus tissue nTPM via the HPA API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets Platform · Databases 2026What this evidence cannot show
DepMap release version not stated by the API. All values use Ensembl ENSG00000166477; an earlier run in this project used an identifier that resolved to ITPRID2 and produced data for the wrong gene.
Evidence that argues against this (1)
- The contrast with PAF1, CTR9 and CDC73 is the finding and it argues that the PAF1 complex is not required as a unit: if three subunits are common-essential and LEO1 is not, then either LEO1 is peripheral or the complex functions without it. Oncofusion knowledge graph (internal analysis) 2026
- E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset
Across 54 DepMap leukemia lines LEO1 correlates with MEN1 at r = 0.302 (95% CI 0.049-0.539, permutation p = 0.026), which does not survive Holm correction across the 16 genes tested (Holm p = 0.286).
Leukemia-restricted co-dependency with MEN1, bootstrap and permutation testing; analyses/wrad-discrimination/ in this project · Broad Institute DepMap; Open Targets Platform; analysis run by this project · Database and derived analysis 2026What this evidence cannot show
Our own computation in 54 lines, failing multiple-testing correction. This is a nominal result and should not be cited as a co-dependency. It is recorded because the accompanying essentiality asymmetry within PAF1C makes it worth revisiting with more lines, not because it is significant.
Evidence that argues against this (1)
- Same objection as for the other sub-threshold correlations in this beat: the deeper 2,743-gene variance-matched null with Holm correction leaves only KMT2A, PSIP1, DOT1L, FLT3, MEF2C and KAT7 standing, with MEIS1 already failing at Holm 0.067. LEO1's r = 0.302 at Holm 0.286 in the 16-gene panel is well below the genes that fail in the deep pool, so it should not be described as a signal of any kind. Broad Institute DepMap; Open Targets Platform; analysis run by this project 2026
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
LEO1 has no domain annotated in UniProt and is resolved structurally only within Pol II elongation-complex cryo-EM models such as 6TED, 7OPC and 8A3Y.
UniProtKB Q8WVC0 (LEO1_HUMAN) feature table and PDB cross-references; RCSB entries 6TED, 7OPC and 8A3Y verified via the RCSB data API · UniProt Consortium; RCSB Protein Data Bank · Databases 2026What this evidence cannot show
LEO1 is largely intrinsically disordered, so the absence of an isolated structure reflects the protein rather than a gap in effort.
Evidence that argues against this (1)
- No annotated domain and structure only inside cryo-EM elongation complexes means there is no isolated target site and no independent model of the protein. RCSB PDB 2026
Counter-evidence: Leo1-Paf1 behaves as a separable subcomplex that antagonises heterochromatin spreading, so LEO1 is not simply a constitutive activating subunit
constitutive PAF1C subunit; the only one not pan-essential
nominal leukemia correlation r=0.30, fails Holm
unflagged import: PMID 20541477 is murine MLL-AF9
LEO1 and CDC73 peaks over the PRMT5 TSS in THP-1