NELFB (COBRA1) — the NELF scaffold, and the single least KMT2A-selective gene of the sixty least selective in the genome
also called NELFB · COBRA1 · NELF-B · KIAA1182 · Negative elongation factor B · cofactor of BRCA1
NELFB is the scaffold that holds the pausing brake together. Of nearly eighteen thousand human genes, it is one of the sixty that KMT2A-rearranged leukaemia cells need least compared with other leukaemia cells — the strongest single anti-dependency in the whole pausing machinery.
The same thing, for a scientist
NELFB (Q8WX92, 628 aa; historically COBRA1, 'cofactor of BRCA1') is the scaffolding subunit of the four-part NELF complex that, with DSIF, enforces promoter-proximal pausing and is displaced from the Pol II funnel by PAF at pause release [E1][E2]. It has **no annotated domains** outside disordered termini (aa 1-40 and 596-628), consistent with a scaffold [E3]. The KMT2A literature contains nothing functional about it: `(MLL OR KMT2A) AND (NELFB OR COBRA1 OR NELF-B)` returns **2 records**, both reviews — a CDK9 review and an Hsp90-in-cancer review that mentions trithorax/MLL and negative elongation factor in separate sentences about Hsp90 clients [E4]. The one quantitative statement available is the project's genome-wide scan, where NELFB ranks **17,671 of 17,728 (99.678th percentile)** with a difference of **+0.2650** — KMT2A-rearranged mean -1.2954 against other-leukaemia -1.5604 — on a pan-essentiality of -1.4051 [E5]. It is the most extreme anti-dependency of any factor in this beat.
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.
What the number means and what it does not
NELFB is required by essentially every cell (pan-essentiality -1.41). The KMT2A-rearranged lines still die without it — their mean is -1.30. What the scan says is only that they die slightly less than other leukaemia lines do, by 0.265 of a Chronos unit 5.
Two readings are available and this entry does not choose between them:
- Biological. A cell whose oncogenic programme depends on constitutive elongation has less to lose from removing a brake it is already overriding. That reading predicts a low pausing index at fusion target genes, and it is carried as
hyp-pause-axis-asymmetry-kmt2a-r. - Artefactual. At -1.4 pan-essentiality the assay is near its floor, and a difference between -1.30 and -1.56 is a difference between two near-complete killing effects. NELFCD, in the same obligate complex, sits at the 36th percentile 5, which is what noise looks like.
The second reading has the stronger prior. The entry's confidence is weak for that reason.
The COBRA1 name, and why it matters for searching
NELFB was described as COBRA1, cofactor of BRCA1, and a large fraction of its older literature is indexed under that symbol rather than under NELFB. This beat searched both, plus NELF-B, and still found only two records against MLL/KMT2A 4.
That is worth stating because the project has been caught by exactly this before: for the septin fusion partners, the retired symbol returned twenty records where the current symbol returned one. Here the alias search did not change the answer, which makes the counted absence more trustworthy than it would otherwise be — but it is still a floor, not a measurement.
Cell type, cell state, localisation, epigenetics
Every axis the beat asks for is not established for NELFB in KMT2A-rearranged disease: no cell type studied, no cell state, no subnuclear localisation, and no epigenetic readout because NELF has no histone-modifying activity. Subcellular localisation is nuclear 3. Its position in the mechanism — present in the paused state, displaced at pause release 12 — is the only thing that can be said with confidence, and it is said about NELF as a complex rather than about this subunit.
| uniprot | Q8WX92 |
|---|---|
| gene symbol | NELFB |
| protein name | Negative elongation factor B |
| length AA | 628 |
| alphafold ID | AF-Q8WX92-F1 |
| accession resolution | UniProt REST query gene_exact:NELFB AND organism_id:9606 AND reviewed:true, run 2026-09-19; one reviewed hit; primary gene name read back as NELFB and length 628 confirmed from the same fetched record. |
| complex | NELF (negative elongation factor), with NELFA, NELFCD and NELFE |
| domains note | UniProt annotates no domains for NELFB outside disordered termini. No domain lane is contributed rather than inventing boundaries. |
| classification | NOT a documented interactor of KMT2A::AFF1; pausing machinery with a counted absence and an extreme anti-dependency signal |
| interaction evidence class | cryo-EM of reconstituted Pol II complexes; unbiased DepMap scan |
| shown for fusion | none |
| epigenetic readout | none - NELF has no histone-modifying activity |
aliases retired or alternate
[ "COBRA1", "NELF-B", "KIAA1182" ]
complex partners
[ "gene-nelfe" ]
domains
[]
localization
{
"subcellular": "nucleus",
"subnuclear": "not established"
}essentiality
{
"depmap_scan": "analyses/depmap-kmt2a-selective-scan-full",
"pan_essentiality_all_lines": -1.4051,
"n_all_lines": 1208,
"mean_kmt2a_rearranged": -1.2954,
"mean_other_leukemia": -1.5604,
"kmt2a_selectivity_difference": 0.265,
"rank": 17671,
"n_scanned": 17728,
"percentile": 99.678,
"interpretation": "the most extreme anti-dependency in this beat; most likely a floor artefact, carried as a lead not a finding"
}enumeration record count
{
"query": "(MLL OR KMT2A) AND (NELFB OR COBRA1 OR NELF-B)",
"records": 2,
"both_reviews": true,
"date": "2026-09-19"
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -1.2954,
"chronos_mean_other_leukaemia": -1.5604,
"difference": 0.265,
"pan_essentiality_all_lines": -1.4051,
"selectivity_rank": 17671,
"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."
}- Pan-essentiality -1.41: any NELFB-directed intervention is a general transcription poison.
- The dependency direction is wrong for a target - KMT2A-rearranged cells need NELFB less, not more.
- The main hazard in this entry is that an extreme percentile rank reads as a discovery. It is a difference between two lethal effects at the assay floor and should not leave this page as anything stronger.
- Does the NELFB anti-dependency survive permutation testing, lineage conditioning and line normalisation? Three analyses this project already has scripts for would settle whether this entry describes anything.
- Hsp90 is reported to chaperone both trithorax/MLL and NELF. Is Hsp90 a shared handler, and does that explain any of this?
- What is the pausing index at KMT2A::AFF1 target genes? Without that measurement the entire anti-dependency interpretation is untethered.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In the cryo-EM structure of the paused transcription complex Pol II-DSIF-NELF at 3.2 A, NELF binds the polymerase funnel, bridges two mobile polymerase modules and contacts the trigger loop, restraining the Pol II mobility required for pause release, and prevents binding of the anti-pausing factor TFIIS.
Structure of paused transcription complex Pol II-DSIF-NELF · Vos SM, Farnung L, Urlaub H, Cramer P · Nature 560(7720):601-606 2018What this evidence cannot show
Abstract fetched and read on 2026-09-19; full text not read. Reconstituted complex with pig Pol II, no chromatin, no leukaemia. The abstract describes NELF as a complex and does not attribute contacts to NELFB specifically, so nothing here is subunit-resolved.
Evidence that argues against this (1)
- That the structure cannot resolve NELFB's individual contribution is precisely why this entry's dependency observation has no mechanistic anchor. A subunit whose role is 'scaffold' and whose structure contributes no named contact is the hardest kind of node to reason about, and a dependency difference attributed to it could be about complex integrity rather than about any NELFB-specific function. UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In the activated elongation complex Pol II-DSIF-PAF-SPT6, PAF displaces NELF from the Pol II funnel for pause release, while DSIF is retained and its RNA clamp is opened by SPT6 after P-TEFb phosphorylates the Pol II CTD linker.
Structure of activated transcription complex Pol II-DSIF-PAF-SPT6 · Vos SM, Farnung L, Boehning M, Wigge C, Linden A, Urlaub H, Cramer P · Nature 560(7720):607-612 2018What this evidence cannot show
Abstract fetched and read on 2026-09-19; full text not read. Reconstituted, chromatin-free, pig Pol II. The displacement is inferred from comparing two static structures rather than observed kinetically.
Evidence that argues against this (1)
- This mechanism makes NELF removal the definition of pause release, which means a cell that needs NELF less is not obviously a cell with less pausing - it could equally be a cell that removes NELF more easily and therefore tolerates having less of it. The two interpretations make opposite predictions about pausing index and the entry cannot distinguish them. Vos SM et al. 2018
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProtKB Q8WX92 (NELFB_HUMAN, Negative elongation factor B) is 628 aa and carries no annotated domains, with disordered regions at aa 1-40 and 596-628.
UniProtKB Q8WX92 (NELFB_HUMAN), Negative elongation factor B · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026What this evidence cannot show
Record fetched 2026-09-19; primary gene name read back as NELFB and length 628 confirmed from the same fetched record. Absence of annotated domains reflects curation, not an absence of structure: NELFB is resolved in the cryo-EM complex.
Evidence that argues against this (1)
- Because NELFB has no annotated domain to give coordinates for, this entry contributes no domain lane to the 3D viewer, and any attempt to place one would be invented. That is a limitation of the entry rather than of the protein. Vos SM et al. 2018
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review
As of 2026-09-19, PubMed returns 2 records for '(MLL OR KMT2A) AND (NELFB OR COBRA1 OR NELF-B)'. Both are reviews: a CDK9 signalling review, and an Hsp90-in-cancer review that mentions trithorax/MLL and negative elongation factor as separate Hsp90-influenced transcriptional mechanisms. Neither reports a NELFB-KMT2A interaction or any functional test in a KMT2A-rearranged model.
Hsp90 in Cancer: Transcriptional Roles in the Nucleus · Calderwood SK, Neckers L · Advances in Cancer Research 129:89-106 2015What this evidence cannot show
Abstract fetched and read on 2026-09-19. This review is cited to document what the retrieved record IS, not for any claim it makes. It states that Hsp90 influences transcription by modulating histone modification via its clients SMYD3 and trithorax/MLL, and separately by regulating Pol II processivity through negative elongation factor - two different mechanisms in one sentence, which is exactly the co-occurrence that makes an enumeration hit look meaningful when it is not.
Evidence that argues against this (1)
- There is a real claim buried in this review that this entry is not pursuing: that Hsp90 chaperones both MLL and NELF. If Hsp90 is a shared client-handler for the fusion and the pausing brake, then an Hsp90 inhibitor would perturb both simultaneously, and that is a genuine mechanistic link between NELF and MLL that no query in this beat was designed to find. Bacon CW et al. 2018
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
In the project's genome-wide KMT2A-rearranged selectivity scan of 17,728 genes, NELFB ranks 17,671 (99.678th percentile) with a difference of +0.2650 (KMT2A-rearranged mean -1.2954 against other-leukaemia mean -1.5604) and a pan-essentiality of -1.4051 across 1,208 lines. In the same scan the other NELF subunits score NELFA +0.2403 (rank 17,650), NELFE +0.0583 (rank 15,340) and NELFCD -0.0208 (rank 6,425).
Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap Chronos via Open Targets) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026What this evidence cannot show
All four rows read out of analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-19 in one pass. Eleven KMT2A-rearranged against 43 other leukaemia lines, AML-heavy, none infant-derived. At a pan-essentiality of -1.41 this is a difference between two near-lethal effects and floor compression is severe; the rank is not permutation-tested for this gene.
Evidence that argues against this (1)
- NELFCD, a subunit of the same obligate complex, sits at the 36th percentile. A genuine complex-level effect should move all four subunits in one direction, and it does not. On the evidence available, the simplest explanation for NELFB's extreme rank is assay noise at the essentiality floor rather than biology. Vos SM et al. 2018
scaffold subunit; the most extreme anti-dependency in this beat
NELF displaced at pause release, scores least-required (rank 17,671)