SEPTIN6 (septin-6) — cytoskeletal GTPase, KMT2A fusion partner in t(X;11)(q24;q23)
also called SEPT6 · septin-6 · KIAA0128 · SEP2
Septin-6 is one of a family of proteins that bind the energy molecule GTP and snap together into filaments, forming part of the cell's internal scaffolding. It has no ability to read or write on DNA, which is why finding it fused to a gene-control protein in leukaemia was so surprising.
The same thing, for a scientist
SEPTIN6 (UniProt Q14141, SEPT6_HUMAN, 434 aa) is a group-II septin: a P-loop NTPase with a septin-type G domain at aa 39-305 carrying the G1/P-loop (49-56), G3 (101-104) and G4 (184-187) motifs, followed by a coiled coil at aa 321-409 [E1]. Septins heteropolymerise into non-polar filaments; in the human SEPT2-SEPT6-SEPT7 heterotrimer the assembly is driven by the nucleotide-binding G interface and the N/C extensions, and the predicted coiled coils were shown by crystallography and electron microscopy NOT to be required for complex or filament formation [E2]. That matters for the leukaemia question, because in the MLL-SEPT6 fusion the coiled coil IS individually required for transformation [E3] -- the fusion therefore does not simply borrow the native assembly mechanism. Loss of function of SEPTIN6 itself is remarkably tolerated: Sept6-null mice have no gross abnormality, no cytokinesis defect and no spontaneous malignancy, and losing Sept6 does not change the disease MLL-SEPT6 induces [E3]. In this project's genome-wide DepMap scan SEPTIN6 is not a dependency in any direction: mean Chronos effect +0.04 across 1090 lines, and it ranks 14,924 of 17,728 for KMT2A selectivity (84th percentile, i.e. if anything slightly LESS required in KMT2A-rearranged lines) [E4].
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.
Why a septin is a strange thing to find on chromatin
Septins are the fourth cytoskeletal system. They are GTP-binding proteins that assemble into homo- and hetero-oligomers and filaments whose architecture differs fundamentally from actin, tubulin and intermediate filaments: an extended G domain forms a universal bipolar polymer building block, oligomerising through conserved interactions between adjacent nucleotide-binding sites and through the N- and C-terminal extensions, with asymmetrical heterotrimers associating head-to-head into a non-polarised hexameric unit 2. There is no chromatin-binding domain, no bromodomain, no YEATS domain, no transactivation domain and no known nuclear function in the canonical annotation 1. The protein's normal residence is the cytoplasm 5.
What the fusion keeps, and what that means
KMT2A::SEPTIN6 retains almost the entire septin ORF, so both the G domain and the coiled coil are present in the oncoprotein 5. The mutational dissection showed each is separately necessary 3. Read against the native assembly data 2 this is informative rather than merely redundant: the coiled coil is dispensable for normal septin filament formation but indispensable for fusion-driven transformation, which means the fusion is not simply reconstituting a septin filament in the nucleus.
Essentiality and the toxicity question
Two independent lines say SEPTIN6 loss is well tolerated. Genetically, Sept6-null mice develop normally and show no cytokinesis phenotype, and even co-depleting the close homologue Sept11 does nothing, which the authors attribute to redundancy in the septin system 3. In cell lines, DepMap Chronos scores SEPTIN6 at +0.04 mean effect across 1090 lines -- not essential anywhere -- with a KMT2A-selectivity rank of 14,924 of 17,728 4.
This cuts both ways for drug discovery. It removes the obvious objection that a septin-directed agent must be catastrophically toxic. It also removes the hope that the wild-type partner allele is itself a dependency in septin-fusion leukaemia. Note the hard limit on the DepMap reading: no KMT2A-septin-fusion cell line exists in the panel, so this is wild-type SEPTIN6 measured in leukaemias driven by other partners.
| uniprot | Q14141 |
|---|---|
| uniprot verified | Q14141 = SEPT6_HUMAN, PRIMARY gene name SEPTIN6, 434 aa, Homo sapiens. Fetched from the UniProt REST API on 2026-09-19 and the primary gene name read back rather than trusting a gene_exact synonym match. Sequence length agrees with the value asserted here. |
| length AA | 434 |
| gene symbol note | Renamed SEPT6 -> SEPTIN6 by HGNC. Both symbols must be searched: a PubMed [Title/Abstract] search for 'SEPTIN6' with MLL/KMT2A returns 5 records while 'SEPT6' returns 19, and the two sets overlap only partly. |
| PDB note | 6UPA = crystal structure of the GTPase domain of the human SEPTIN2/SEPTIN6 heterocomplex, 2.51 A; 2QAG = human septin 2/6/7 trimer, 4.0 A. Both verified against the RCSB entry API on 2026-09-19. No structure of any SEPTIN6 coiled coil, and none of a KMT2A fusion. |
| alphafold ID | AF-Q14141-F1 |
| localization | cytoplasm in the normal protein; nuclear speckles when fused to the KMT2A N-terminus |
| family | septin, group II (SEPT6 group) |
PDB IDS
[ "6UPA", "2QAG" ]
domains — the numbers behind the chart
[
{
"name": "Septin-type G domain",
"start": 39,
"end": 305
},
{
"name": "G1/P-loop motif",
"start": 49,
"end": 56
},
{
"name": "G3 motif",
"start": 101,
"end": 104
},
{
"name": "G4 motif",
"start": 184,
"end": 187
},
{
"name": "Coiled coil",
"start": 321,
"end": 409
}
]essentiality
{
"depmap_common_essential": false,
"chronos_mean": 0.038,
"chronos_n_lines": 1090,
"kmt2a_selectivity_rank": 14924,
"kmt2a_selectivity_of": 17728,
"mouse_ko": "Sept6-null mice viable, no gross abnormality, no cytokinesis defect, no spontaneous malignancy; MLL-SEPT6 disease unchanged on the null background"
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": 0.0597,
"chronos_mean_other_leukaemia": 0.0074,
"difference": 0.0523,
"pan_essentiality_all_lines": 0.0383,
"selectivity_rank": 14924,
"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."
}- A near-zero DepMap score and a viable knockout mouse together mean the wild-type partner is not a therapeutic handle, and a drug that simply removed septin-6 would be expected to do nothing to a septin-fusion leukaemia.
- Septin redundancy is the central obstacle: the paralogue that buffers the knockout would also buffer a selective inhibitor, so any septin-directed agent would need to hit the fusion's assembled interface rather than the protein.
- Does the MLL-SEPT6 fusion form a septin-like filament in the nucleus, or an unrelated oligomer? No structural or imaging work has distinguished these.
- Does the fusion incorporate endogenous septin partners (SEPT2, SEPT7, SEPT11) into a hetero-oligomer, and would depleting those partners break it? This is the most obvious untried genetic test and would also explain why the coiled coil matters.
- Is the GTP requirement a nucleotide-state requirement or merely a folding requirement? The S56N result is consistent with either.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Human septin-6 is UniProt Q14141 (SEPT6_HUMAN), primary gene name SEPTIN6, 434 aa, with a septin-type G domain at aa 39-305, G1/P-loop at 49-56, G3 at 101-104, G4 at 184-187, a coiled coil at aa 321-409, a disordered C-terminal tail at 405-434, and GTP-binding sites at 49-56, 104, 185-193, 239 and 254.
UniProtKB Q14141 (SEPT6_HUMAN) Septin-6, Homo sapiens, 434 aa · UniProt Consortium · UniProtKB 2026What this evidence cannot show
Canonical isoform. The founding fusion paper reports SEPTIN6 encodes at least two protein types by alternative splicing, so residue numbers are isoform-specific. Resolved by reading back the PRIMARY gene name: the retired symbol SEPT6 is only a synonym.
Evidence that argues against this (1)
- The coiled-coil annotation should not be read as an assembly module: crystallography and EM of the human SEPT2-SEPT6-SEPT7 complex showed the predicted coiled coils are not involved in, and not required for, complex or filament formation. Sirajuddin M et al. 2007
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
The structures of the human SEPT2 G domain and the heterotrimeric SEPT2-SEPT6-SEPT7 complex reveal a universal bipolar polymer building block composed of an extended G domain that oligomerises through conserved interactions between adjacent nucleotide-binding sites and through the N- and C-terminal extensions; X-ray crystallography and electron microscopy showed the predicted coiled coils are not involved in or required for complex or filament formation, and the asymmetrical heterotrimers associate head-to-head into a non-polarised hexameric unit whose architecture differs fundamentally from other cytoskeletal structures.
Structural insight into filament formation by mammalian septins. · Sirajuddin M, Farkasovsky M, Hauer F, et al. · Nature 2007What this evidence cannot show
Structures of SEPT2/6/7 at 4.0 A for the trimer (PDB 2QAG) with higher-resolution G-domain structures; the coiled-coil conclusion is partly a negative result from constructs and EM rather than a resolved coiled-coil-deleted structure.
Evidence that argues against this (1)
- In the leukaemic fusion context the coiled coil behaves as if it were required: deleting the SEPT6 coiled coil abolished myeloid immortalisation by MLL-SEPT6 and abolished detectable self-association of the fusion protein. Either the fusion uses a different assembly mode from the native filament, or one of the two results is construct-specific. Ono R et al. 2005
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Sept6-deficient mice exhibited neither gross abnormalities, changes in cytokinesis nor spontaneous malignancy, Sept6 deficiency caused no quantitative change in other septins and no additional change on the Sept4-deficient background, depletion of the close homologue Sept11 did not affect Sept6-null cells, and loss of Sept6 did not alter the myeloproliferative disease induced by MLL-SEPT6 — the first demonstration that disrupting an MLL 11q23 translocation partner gene does not contribute to leukemogenesis by the fusion.
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 knockout, gross phenotype and disease latency as readouts. The authors themselves attribute the null phenotype to a high degree of redundancy in the septin system.
Evidence that argues against this (1)
- Human data show partner-gene dosage is not untouched: SEPT6 transcript is significantly down-regulated 1.7-fold (p=0.002) in MLL-SEPT6 patient leukaemia, and MLL-SEPT2 and MLL-SEPT6 neoplasias cluster together by septin-expression change, so a dosage effect in patients is not excluded by a mouse knockout. Santos J et al. 2010
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
In a genome-wide DepMap CRISPR (Chronos) scan of 17,728 genes, SEPTIN6 had a mean gene effect of +0.038 across 1090 lines (not essential), a KMT2A-rearranged group mean of +0.060 versus +0.007 in other leukaemia lines, and ranked 14,924 of 17,728 for KMT2A selectivity (84.2nd percentile) — i.e. it is, if anything, marginally less required in KMT2A-rearranged lines.
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
Decisive limitation: no KMT2A-septin-fusion cell line exists in the DepMap panel, so this measures wild-type SEPTIN6 in leukaemias driven by other KMT2A partners and says nothing about SEPTIN6 dependency in a septin-fusion leukaemia. Chronos scores near zero are also where noise dominates, and the KMT2A-rearranged group is only 11 lines.
Evidence that argues against this (1)
- A near-zero CRISPR score cannot exclude a requirement that is buffered by paralogues; the same redundancy that produced the null mouse phenotype would also produce a null CRISPR score for a single septin gene, so this evidence is consistent with, not independent of, the knockout result. Ono R et al. 2005
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
SEPTIN6 is ubiquitously expressed, its protein normally resides in the cytoplasm, and the MLL-SEPTIN6 fusion protein contains almost the entire septin protein and relocalises to nuclear speckles while overexpressed SEPT6 alone remains cytoplasmic.
Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. · Ono R, Nakajima H, Ozaki K, et al. · J Clin Invest 2005What this evidence cannot show
Localisation determined by confocal immunofluorescence in transiently transfected 293T cells, not in leukaemic blasts or patient material.
Evidence that argues against this (1)
- Expression is not uniform across tissues as 'ubiquitous' implies: the founding survey found the ~2.3, 3.1 and 4.6 kb SEPTIN6 transcripts in fetal lung, liver and brain and in all adult tissues EXCEPT brain, while a ~2.7 kb transcript was detected only in fetal heart and adult brain, so isoform usage is tissue-restricted. Ono R et al. 2002
almost the entire septin-6 ORF, G domain plus coiled coil
- ← fuses withKMT2A / MLL1 — the gene that breaks
t(X;11)(q24;q23) and cryptic ins(X;11)
- fuses with →KMT2A / MLL1 — the gene that breaks
KMT2A::SEPTIN6, t(X;11)(q24;q23)
- ← related toSEPTIN9 (septin-9 / MSF) — cytoskeletal GTPase, KMT2A fusion partner in t(11;17)(q23;q25)
both KMT2A-partner septins; SEPTIN9 has no annotated coiled coil, SEPTIN6 does
almost the entire ORF is retained in the fusion
closest homologues; genetically buffer each other
native SEPT2-SEPT6-SEPT7 heterotrimer