SEPTIN11 (septin-11) — KMT2A fusion partner at 4q21, adjacent to AFF1
also called SEPT11 · septin-11
Septin-11 is the closest relative of septin-6 and sits on chromosome 4 just next to AFF1, the commonest KMT2A partner of all. That accident of position means a KMT2A break joining it looks, under the microscope, exactly like the famous t(4;11).
The same thing, for a scientist
SEPTIN11 (UniProt Q9NVA2, SEP11_HUMAN, 429 aa) has a septin-type G domain at aa 38-304 with G1/P-loop 48-55, G3 100-103 and G4 183-186, the longest coiled coil of any KMT2A-partner septin at aa 320-415, and a disordered C-terminus at 398-429 [E1]. It is the closest homologue of SEPTIN6, and the genetic test of that relationship is informative: depleting Sept11 in Sept6-null cells produced no phenotype, which the authors read as redundancy within the septin system [E4]. Its genomic position matters more than its biochemistry so far — SEPTIN11 lies within 250 kb proximal to AFF1 at 4q21, so KMT2A::SEPTIN11 produces a t(4;11)(q21;q23) karyotype indistinguishable from KMT2A::AFF1 and is separable only by molecular typing.
No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.
Architecture
SEPTIN11 is a 429 aa septin: G domain at 38-304 (G1/P-loop 48-55, G3 100-103, G4 183-186), coiled coil at 320-415 and a disordered tail at 398-429 1. Its 96-residue coiled coil is the longest among the KMT2A-partner septins (SEPTIN6 89, SEPTIN5 32, SEPTIN2 and SEPTIN9 none annotated). Native septin assembly does not use those helices 2, so the spread in coiled-coil length across the five partners is a free natural experiment on whether the fusion's requirement for one is real.
Dependency and tolerance of loss
In this project's genome-wide DepMap CRISPR (Chronos) scan the gene is not a selective requirement in KMT2A-rearranged leukaemia lines 3. The decisive limitation is that no KMT2A-septin-fusion cell line exists in the DepMap panel, so every septin score in this beat measures the wild-type gene in leukaemias driven by other partners. Separately, the septin system is redundant enough that a null mouse for one member (Sept6) has no phenotype and co-depleting its closest homologue adds nothing 4 — the same redundancy would blunt a single-gene CRISPR score, so the two negative results are not independent.
| uniprot | Q9NVA2 |
|---|---|
| uniprot verified | Q9NVA2 = SEP11_HUMAN, PRIMARY gene name SEPTIN11, 429 aa, Homo sapiens. Fetched from the UniProt REST API on 2026-09-19 and the primary gene name read back. |
| length AA | 429 |
| family | septin, group II; closest homologue of SEPTIN6 |
| gene symbol note | The septin family was systematically renamed by HGNC (SEPT2/5/6/9/11 -> SEPTIN2/5/6/9/11). Both symbols must be searched; PubMed intersections with MLL/KMT2A differ substantially between the old and new symbols. |
domains — the numbers behind the chart
[
{
"name": "Septin-type G domain",
"start": 38,
"end": 304
},
{
"name": "G1/P-loop motif",
"start": 48,
"end": 55
},
{
"name": "G3 motif",
"start": 100,
"end": 103
},
{
"name": "G4 motif",
"start": 183,
"end": 186
},
{
"name": "Coiled coil",
"start": 320,
"end": 415
}
]essentiality
{
"depmap_common_essential": false
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.0402,
"chronos_mean_other_leukaemia": -0.0986,
"difference": 0.0584,
"pan_essentiality_all_lines": -0.1488,
"selectivity_rank": 15347,
"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."
}- Because this fusion produces an ordinary-looking t(4;11), the practical risk is that patients carrying it are counted, stratified and treated as KMT2A::AFF1, which both mistreats them and contaminates AFF1 cohorts.
- Any inhibitor of a septin coiled coil would have to contend with the fact that the coiled coil is dispensable for normal septin function, so on-target normal-tissue effects may be minimal — but so may on-target efficacy, since the same structural work says the coiled coil is not where septin assembly happens.
- SEPTIN11 has the longest coiled coil of the partner septins and SEPTIN5 the shortest. A side-by-side transformation assay across the five partner septins is the single cheapest experiment that would settle whether the coiled coil is the conserved element.
- SEPTIN11 and SEPTIN6 are close homologues and buffer each other genetically. Does the MLL-SEPT6 fusion protein recruit endogenous SEPTIN11 into its oligomer, and is that why the coiled coil is required?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Human septin11 is UniProt Q9NVA2 (SEP11_HUMAN), primary gene name SEPTIN11, 429 aa, with the domain architecture recorded in data.domains.
UniProtKB Q9NVA2 (SEP11_HUMAN) 429 aa, Homo sapiens · UniProt Consortium · UniProtKB 2026What this evidence cannot show
Canonical isoform. Coordinates fetched from the UniProt REST record on 2026-09-19; the PRIMARY gene name was read back rather than relying on a gene_exact match, which for septins is unusually dangerous because the whole family was renamed (SEPT9 -> SEPTIN9 and so on) and every record still carries the retired symbol as a synonym.
Evidence that argues against this (1)
- UniProt coiled-coil annotations on septins are prediction-driven and should not be read as assembly modules: crystallography and electron microscopy of the human SEPT2-SEPT6-SEPT7 complex showed the predicted coiled coils are not involved in, and not required for, complex or filament formation, which proceeds through the nucleotide-binding G interface and the N/C extensions. Sirajuddin M et al. 2007
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Mammalian septins are GTP-binding proteins that assemble into homo- and hetero-oligomers and filaments through an extended G domain forming a universal bipolar polymer building block, via conserved interactions between adjacent nucleotide-binding sites and the N- and C-terminal extensions, producing an architecture fundamentally different from actin, tubulin and intermediate filaments.
Structural insight into filament formation by mammalian septins. · Sirajuddin M, Farkasovsky M, Hauer F, et al. · Nature 2007What this evidence cannot show
Structural work on the SEPT2/6/7 complex; extrapolated here to other family members on sequence and architectural homology.
Evidence that argues against this (1)
- The fusion context does not obey this architecture: in MLL-SEPT6 the coiled coil is individually required for both self-association and transformation, which native filament assembly says it should not be. Ono R et al. 2005
- E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset
In a genome-wide DepMap CRISPR (Chronos) scan, SEPTIN11 had a mean gene effect of -0.149 across 1090 lines, a KMT2A-rearranged group mean of -0.040 versus -0.099 in other leukaemia lines, and ranked 15,347 of 17,728 for KMT2A selectivity (86.6th percentile).
DepMap CRISPR (Chronos) genome-wide KMT2A-selectivity scan of 17,728 protein-coding genes, 11 Cellosaurus-annotated KMT2A-rearranged leukaemia lines vs other leukaemia lines (analyses/depmap-kmt2a-selective-scan-full/results.json, all_results; septin/ABI1/MLLT11 rows looked up for this beat) · Broad Institute DepMap; Cellosaurus; Open Targets Platform; scan run by this project · Database and derived analysis 2026What this evidence cannot show
No KMT2A-septin-fusion line exists in the DepMap panel; the KMT2A-rearranged group is 11 lines; Chronos values near zero are noise-dominated. Reported to close a question, not to open one.
Evidence that argues against this (1)
- A single-gene CRISPR score cannot detect a requirement buffered by the other twelve septins; the same redundancy that left Sept6-null mice phenotypically normal would produce a null score here. Ono R et al. 2005
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The septin system is highly redundant: Sept6-null mice show no gross abnormality, no cytokinesis change and no spontaneous malignancy, Sept6 loss does not alter MLL-SEPT6-induced disease, and depleting the close homologue Sept11 does not affect Sept6-null cells.
Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4. · Ono R, Ihara M, Nakajima H, et al. · Mol Cell Biol 2005What this evidence cannot show
Mouse genetics with gross phenotype as readout; demonstrated for Sept6 and Sept11, extended here to the family as an argument about redundancy rather than a measurement on this particular gene.
Evidence that argues against this (1)
- Redundancy is not complete at the expression level in patients: septin transcript changes distinguish MLL-SEPT2 and MLL-SEPT6 leukaemias, which cluster together and apart from other AML subgroups by septin-expression profile, so the family is not interchangeable in vivo. Santos J et al. 2010
- ← fuses withKMT2A / MLL1 — the gene that breaks
t(4;11)(q21;q23), impersonating KMT2A::AFF1
G domain plus the longest partner-septin coiled coil
closest homologues; genetically buffer each other