IKBKG (NEMO) — the scaffold that makes the canonical complex a complex, and a symbol that returns ZERO records in this disease
also called IKBKG · NEMO · IKK-gamma · IKKG · FIP-3 · NF-kappa-B essential modulator · Q9Y6K9
NEMO is not a kinase; it is the clamp that holds the two IKK kinases together and lets incoming signals switch them on. It is needed for MLL leukaemia cells to grow, but that single result sits inside one figure of one paper and no study has ever been written about NEMO in this disease.
The same thing, for a scientist
IKBKG (UniProt Q9Y6K9, 419 aa, primary gene name read back) is the non-catalytic regulatory subunit — NEMO — of the canonical IKK complex. It contains no kinase domain; it binds polyubiquitin chains generated upstream by TRAF6 and LUBAC and thereby couples receptor engagement to IKKa/IKKb activation. **It is strictly canonical**: the non-canonical NIK/IKKa route to p100 processing is NEMO-independent, which makes IKBKG the cleanest available genetic handle for hitting the canonical arm without touching the arm that suppresses MLL-AF9 leukaemia. **All of its leukaemia evidence is one line in one paper.** IKKg was among the 33 phosphoregulator hits, and shRNA reduction of Ikkg decreased growth and clonogenicity in MLL-oncogene-transduced and MLL AML cells but not in E2A-PBX1-transduced cells or normal haematopoietic progenitors — 'to a lesser extent' than Ikkb [E1]. **And then the absence.** A PubMed search over IKBKG, NEMO and both IKK-gamma spellings against KMT2A, MLL and 'mixed-lineage leukemia' returns **0 records** [E2]. The founding paper's Ikkg experiment is not reachable from any symbol-keyed query, because the subunit is named only inside its figures. That is a general lesson about counted absences as much as a fact about NEMO.
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 scaffold is the interesting target here, not a consolation prize
The sign problem that runs through this whole beat is that IKKa serves both arms and pan-IKK chemistry blocks both. NEMO does not have that problem: the NIK/IKKa/p100 route does not use it. A NEMO-directed intervention is therefore the one way in this pathway to test 'canonical only' cleanly.
One such intervention exists in the literature and is a peptide, not a small molecule: the NEMO-binding domain (NBD) peptide, which has been taken through a phase I study by systemic delivery in dogs with spontaneous activated-B-cell-like diffuse large B-cell lymphoma 3. That is not this disease, and it is a peptide with the delivery problems peptides have, but it establishes that the node has been drugged in a living animal and bounds what is known.
The absence is bounded and it is also a warning about absences
Zero records over four symbol spellings 2. But the founding MLL paper does contain an Ikkg knockdown, and it is invisible to that query because the abstract says 'IKK/NF-kB' and the subunit appears only in figure text 1. So the honest statement is: IKBKG has never been the framed subject of a paper in this disease, and it has been measured once inside a paper about the pathway. Any beat writing a counted absence for a complex subunit should expect this shape and search the complex's name as well — the rule the brief records for NSL and Mediator applies verbatim to IKK.
| uniprot | Q9Y6K9 |
|---|---|
| length AA | 419 |
| alphafold ID | AF-Q9Y6K9-F1 |
| resolution note | gene_exact:IKBKG AND organism_id:9606 AND reviewed:true returned 1 reviewed row; gene_primary read back as IKBKG; length 419 aa. |
| pathway arm | canonical only (non-canonical p100 processing is NEMO-independent) |
| catalytic | false |
essentiality
{}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.2097,
"chronos_mean_other_leukaemia": -0.205,
"difference": -0.0047,
"pan_essentiality_all_lines": -0.1766,
"selectivity_rank": 8537,
"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."
}- Germline IKBKG loss-of-function in humans causes immunodeficiency with ectodermal dysplasia, and in females incontinentia pigmenti. That is a strong prior that even partial, reversible blockade in a developing infant carries an immune cost.
- NEMO is the convergence point for essentially all canonical NF-kB input, including the responses that control bacterial and fungal infection. Blocking it is broader than blocking any single receptor upstream.
- The only in vivo drug-like agent at this node is a peptide, with the exposure, stability and marrow-penetration problems peptides carry.
- The entire disease-specific case for this target is one shRNA panel in a mouse myeloid model. Building a therapeutic argument on it would be building on a single figure.
- Does NEMO disruption evict the MLL fusion from chromatin? If it does, it would separate canonical eviction from non-canonical protection in one experiment, which no compound currently used in this field can do.
- Is NEMO loss better tolerated by normal progenitors than IKKb loss? The 2013 screen reports sparing of normal progenitors for all three subunits but with no quantitative comparison.
- Would an NBD-type peptide or a NEMO-directed degrader reach a leukaemic blast in marrow at all? Delivery, not target biology, is the binding constraint here.
- Human IKBKG hypomorphs cause anhidrotic ectodermal dysplasia with immunodeficiency. What does that predict about partial pharmacological NEMO blockade in an infant?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
IKKg was among 33 phosphoregulator candidates whose knockdown impaired growth of MLL-oncogene-transformed myeloid progenitors by 50% or more; genetic reduction of Ikkg by shRNA decreased growth and clonogenicity in MLL-oncogene-transduced cells and MLL AML cells but not in E2A-PBX1-transduced cells or normal haematopoietic progenitors, contributing to a lesser extent than Ikkb.
Epigenetic roles of MLL oncoproteins are dependent on NF-κB. · Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SHK, Lin CH, Figueroa ME, Su J, Lemischka IR, Cleary ML · Cancer Cell 2013What this evidence cannot show
Mouse myeloid progenitors and mouse AML cells. Growth and clonogenicity only - no occupancy, no protein-level NF-kB readout, no lymphoid model, no human cell. The comparison to Ikkb is qualitative. Full text read this session (PMC3816582). This is the entire leukaemia evidence base for IKBKG.
Evidence that argues against this (1)
- NEMO may not be a necessary target even if it is a real dependency. A degrader directed at IKKb alone (with NR4A1) suppresses KMT2A::MLLT3 AML in vivo without touching NEMO, which shows the canonical arm can be disabled therapeutically at a different node - and one that already has chemical matter, which NEMO does not. Maharjan CK et al. 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
Counted absence. (KMT2A OR MLL OR "mixed-lineage leukemia") AND (IKBKG OR NEMO[tiab] OR "IKK gamma"[tiab] OR "IKK-gamma"[tiab]) returns 0 PubMed records. IKBKG has never been named in the title or abstract of a KMT2A or MLL paper.
PubMed E-utilities esearch, db=pubmed, run 2026-09-20 · NCBI · PubMed 2026What this evidence cannot show
querytranslation was read and contained no [UID] artefact, so the zero is genuine for that symbol set. It is nonetheless a false negative about the biology: the 2013 paper measures Ikkg and is unreachable from any subunit symbol because it frames at the level of the complex. Aliases FIP3 and IKKAP1 were not searched.
Evidence that argues against this (1)
- A zero at the symbol level is not a zero at the pathway level, and on this beat that is demonstrable rather than hypothetical: PMID 29320732 studies the non-canonical arm directly in MLL-AF9 leukaemia and is unreachable from any of these subunit symbol queries, because it names the kinase and the pathway rather than the subunit. The count is honest about what was searched and should not be read as evidence that the biology is unstudied - only that it is not indexed under this symbol. Xiu Y et al. 2018
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
A NEMO-binding domain peptide has been delivered systemically in a phase I clinical trial in dogs with spontaneous activated-B-cell-like diffuse large B-cell lymphoma.
A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. · Habineza Ndikuyeze G, Gaurnier-Hausser A, ... Mason NJ · PLoS One 2014What this evidence cannot show
Abstract read this session. Intravenous NBD peptide below 2 mg/kg was safe and inhibited constitutive canonical NF-kB in 6 of 10 dogs, with grade 1 toxicities in 3 and transient subclinical hepatopathy in 1. It is a canine study in activated-B-cell-like DLBCL, not a leukaemia, not paediatric, n=10, single-arm, with biological rather than survival endpoints. Cited only to bound the claim that the NEMO node has been drugged systemically in a living animal; do not read efficacy in leukaemia into it.
Evidence that argues against this (1)
- A phase I trial in dogs with spontaneous ABC-DLBCL is a genuine in-vivo safety signal in a large outbred animal, but it is a different disease with a different NF-kB dependency, and canine dosing does not transfer to infants. Nothing in it addresses KMT2A-rearranged leukaemia, where the non-canonical arm's manipulation points the opposite way. Xiu Y et al. 2018
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt reviewed human record Q9Y6K9 (NEMO_HUMAN) has primary gene name IKBKG and length 419 aa; gene_exact:IKBKG AND organism_id:9606 AND reviewed:true returned exactly one row and gene_primary read back as IKBKG.
UniProtKB entry Q9Y6K9 (NEMO_HUMAN), NF-kappa-B essential modulator · UniProt Consortium · UniProt 2026What this evidence cannot show
Resolved 2026-09-20 with gene_primary requested and all rows read.
Evidence that argues against this (1)
- A reviewed database record fixes the canonical sequence and primary symbol on the date it was read, and nothing more. It does not establish that the protein is expressed in KMT2A-rearranged blasts, which isoform is present, or that the subunit acts in this disease. Accession and length are asserted so that a swap fails verify-accessions.py - a defence this graph needs because IKK-family and NF-kB subunit names collide heavily in the older literature - not because the record carries biological weight. Xiu Y et al. 2018
TESTED, NOT REFUTED: 62 free-text co-occurrences, none in title or abstract with KMT2A (2026-09-20).
NEMO, the non-catalytic ubiquitin-binding scaffold; canonical arm only
Ikkg shRNA reduces growth and clonogenicity of MLL-transformed cells but not normal progenitors
zero records for IKBKG/NEMO in this disease, with the query