SEPTIN5 (septin-5 / CDCrel-1) — KMT2A fusion partner in t(11;22)(q23;q11.2)
also called SEPT5 · CDCrel-1 · PNUTL1 · peanut-like protein 1 · septin-5
Septin-5, originally called CDCrel-1, is a cell-division septin that was the very first septin found fused to KMT2A, in infant twins with leukaemia. It is the shortest of the KMT2A-partner septins and has the shortest self-association helix.
The same thing, for a scientist
SEPTIN5 (UniProt Q99719, SEPT5_HUMAN, 369 aa) is the shortest KMT2A-partner septin: a septin-type G domain at aa 41-314 with G1/P-loop 51-58, G3 108-111 and G4 189-192, and a coiled coil of only 32 residues at aa 338-369 [E1]. Its protein aliases CDCrel-1 and peanut-like protein 1 are the names under which the founding KMT2A fusion was reported, and the gene lies at 22q11.2 within the region commonly deleted in DiGeorge and velocardiofacial syndromes. It has no annotated chromatin-binding activity. In this project's DepMap scan SEPTIN5 is the most KMT2A-leaning of the partner septins at rank 2,433 of 17,728 — a difference of -0.066 Chronos units, which in a scan where MEN1 ranks first with -0.87 is a non-result [E3].
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
SEPTIN5 is a 369 aa septin-type P-loop NTPase: G domain at 41-314, G1/P-loop at 51-58, G3 at 108-111, G4 at 189-192, and a short coiled coil at 338-369 1. The G domain is what native septin filaments polymerise through, via adjacent nucleotide-binding sites and the N/C extensions, in an architecture unlike any other cytoskeletal polymer 2. Almost the entire ORF is retained in KMT2A::SEPTIN5. Note the size of the coiled coil: 32 residues, against 89 for SEPTIN6 and 96 for SEPTIN11, while SEPTIN2 and SEPTIN9 have none annotated at all. If the coiled coil is the transforming element, the five KMT2A-partner septins are not equivalent and should not be treated as one class.
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 | Q99719 |
|---|---|
| uniprot verified | Q99719 = SEPT5_HUMAN, PRIMARY gene name SEPTIN5, 369 aa, Homo sapiens. Fetched from the UniProt REST API on 2026-09-19 and the primary gene name read back. |
| length AA | 369 |
| family | septin, group II (SEPT2/5/... group); maps to 22q11.2 inside the DiGeorge/velocardiofacial deletion interval |
| 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": 41,
"end": 314
},
{
"name": "G1/P-loop motif",
"start": 51,
"end": 58
},
{
"name": "G3 motif",
"start": 108,
"end": 111
},
{
"name": "G4 motif",
"start": 189,
"end": 192
},
{
"name": "Coiled coil",
"start": 338,
"end": 369
}
]essentiality
{
"depmap_common_essential": false
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.1538,
"chronos_mean_other_leukaemia": -0.0878,
"difference": -0.066,
"pan_essentiality_all_lines": -0.1163,
"selectivity_rank": 2433,
"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 drug against a septin self-association surface would act on a protein already present at reduced dosage in the 22q11.2 deletion population, where the safety margin is unmeasured.
- SEPTIN5's DepMap rank is the kind of weak, directionally pleasing signal that becomes a target if it is not stated plainly as noise. It is noise.
- Does coiled-coil length matter? SEPTIN5's is 32 residues against SEPTIN11's 96 and SEPTIN6's 89; the dimerisation model predicts a difference in transforming strength that has never been measured.
- SEPTIN5 is hemizygous in 22q11.2 deletion syndrome. Is there any excess of KMT2A-rearranged leukaemia in that population? Nobody appears to have looked, and the cohorts exist.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Human septin5 is UniProt Q99719 (SEPT5_HUMAN), primary gene name SEPTIN5, 369 aa, with the domain architecture recorded in data.domains.
UniProtKB Q99719 (SEPT5_HUMAN) 369 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, SEPTIN5 had a mean gene effect of -0.116 across 1090 lines, a KMT2A-rearranged group mean of -0.154 versus -0.088 in other leukaemia lines, and ranked 2,433 of 17,728 for KMT2A selectivity (13.7th 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(11;22)(q23;q11.2)
almost the entire ORF retained
both group-II septins and both KMT2A partners