NFKBIA (IkB-alpha) — the switch itself. This graph has entries for everything the switch controls and none for the switch
also called NFKBIA · IkB-alpha · IkBa · IKBA · MAD-3 · NF-kappa-B inhibitor alpha · P25963
IkB-alpha is the brake that holds NF-kB in the cytoplasm; destroying it is what actually flips the switch on. Everything upstream in this pathway exists to destroy it, and everything downstream happens because it was destroyed.
The same thing, for a scientist
NFKBIA (UniProt P25963, 317 aa, primary gene name read back) is the principal inhibitor of canonical NF-kB. It sequesters RELA:p50 in the cytoplasm; IKK phosphorylation of its N-terminal serines targets it for beta-TrCP-mediated ubiquitination and proteasomal degradation, releasing the dimer. **The whole of this beat is the story of one protein being destroyed.** The IKK complex exists to destroy it [E1]; the proteasome inhibitor results in this disease are usually read as preventing its destruction; and the clearest direct measurement in the MLL literature is that **NIK stabilisation upregulates Nfkbia/IkBa together with Tnfaip3/A20, and nuclear RelA falls as a result** [E2]. That last observation is the mechanistic bridge between the two papers this beat is built on: it is how the non-canonical arm represses the canonical arm, and it names IkBa as the executing node. **The absence is stark.** A PubMed search over NFKBIA and three IkB-alpha spellings against KMT2A, MLL and 'mixed-lineage leukemia' returns **2 records**, and title-checking leaves **one** on topic — the non-leukaemic paper showing that wild-type MLL1 is recruited to TNFa-stimulated NF-kB targets in an NF-kB-dependent way [E3][E4]. So IkB-alpha has never been measured in a KMT2A-rearranged cell in any published study this beat could find.
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 the switch deserves an entry and the pathway diagram does not
Everything else in this folder is a thing that acts on IkBa or a thing released by its loss. Without an entry for it, the graph's causal chain has a hole exactly where the state change happens: the reader goes from 'IKK is active' to 'RELA is nuclear' with nothing in between, and the two published interventions that move this axis — proteasome inhibition and NIK stabilisation — both act on IkBa levels rather than on IKK activity 2.
It also carries the cleanest falsifiable prediction in the beat. If IKK inhibition evicts the MLL fusion from chromatin because RELA leaves the promoter, then an IkBa super-repressor (the S32A/S36A non-degradable mutant) should evict it too, with no kinase inhibitor and therefore none of the off-target ambiguity of IKK inhibitors III, IV and VII. That experiment appears nowhere in this literature.
The proteasome complication, stated plainly
Bortezomib is routinely described as an NF-kB inhibitor because it prevents IkBa degradation. In MLL-rearranged leukaemia that description is doubly unsafe. First, bortezomib has been shown to induce NF-kB in several tumour types and in normal PBMCs through calpain-dependent and caspase-independent routes, a point the founding MLL paper itself raises 1. Second, and specific to this disease, proteasome inhibition in pro-B MLL leukaemias works by stabilising MLL-AF4 itself and thereby switching on a latent tumour-suppression programme — a mechanism that has nothing to do with IkBa (mechanism-proteasome-inhibition-splits-by-lineage-in-mll-leukaemia). Citing a bortezomib result as evidence about IkBa in this disease would be wrong in two independent ways.
| uniprot | P25963 |
|---|---|
| length AA | 317 |
| alphafold ID | AF-P25963-F1 |
| resolution note | gene_exact:NFKBIA AND organism_id:9606 AND reviewed:true returned 1 reviewed row; gene_primary read back as NFKBIA; length 317 aa. |
| pathway arm | canonical |
| role | inhibitor; degradation is the activating step |
paralogues checked
[
{
"symbol": "NFKBIB",
"uniprot": "Q15653",
"length_aa": 356
},
{
"symbol": "NFKBIE",
"uniprot": "O00221",
"length_aa": 500
}
]depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.1093,
"chronos_mean_other_leukaemia": -0.108,
"difference": -0.0013,
"pan_essentiality_all_lines": -0.1247,
"selectivity_rank": 8983,
"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."
}- Stabilising IkBa pharmacologically means inhibiting the proteasome or beta-TrCP, neither of which is remotely selective for this pathway, and the proteasome route in MLL pro-B leukaemia works through a completely different mechanism (stabilising MLL-AF4 itself).
- Bortezomib has been reported to induce NF-kB rather than inhibit it in several settings including normal PBMCs, so a proteasome-based argument about IkBa in this disease can be exactly backwards.
- IkBa-mediated restraint of NF-kB is what prevents lethal inflammation. An intervention that mimics permanent IkBa raises the same immunosuppression problem as IKK inhibition, without the target selectivity.
- Does an IkBa super-repressor (S32A/S36A) evict the MLL fusion from chromatin? This is the cleanest test of the whole retention mechanism and it uses no kinase inhibitor, so it carries none of the off-target ambiguity of IKK inhibitors III/IV/VII.
- Is IkBa turnover faster in KMT2A-rearranged blasts than in normal progenitors? If constitutive canonical activation in this disease is IkBa-driven, that is a measurable, cell-autonomous marker and nobody has measured it.
- Does a menin inhibitor change IkBa levels? Menin represses RELA transactivation, and NF-kB drives NFKBIA transcription, so menin loss should raise IkBa as a feedback - which would partly self-limit the RELA liberation hypothesis.
- Do NFKBIB or NFKBIE substitute when IkBa is lost in this lineage? Neither has ever been measured in this disease.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In the canonical NF-kB signalling pathway the IKKa/b/g complex phosphorylates IkBa and triggers its degradation, thereby liberating the NF-kB heterodimer and inducing nuclear translocation. The same paper notes that bortezomib, a proteasome inhibitor widely described as indirectly inhibiting NF-kB by preventing IkBa proteasomal degradation, has been observed to induce rather than inhibit NF-kB in various tumour types and in normal peripheral blood mononuclear cells through calpain-dependent or caspase-independent mechanisms.
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
The pathway description is background in this paper's discussion, not something it measures; the bortezomib caution is a literature review inside a discussion section, with its primary sources not re-fetched here. No IkBa western, no IkBa perturbation and no IkBa measurement of any kind appears anywhere in the paper. Full text read this session (PMC3816582).
Evidence that argues against this (1)
- The canonical cascade as described is textbook pathway biology and is not specific to KMT2A-rearranged disease. Where this pathway has been manipulated in an MLL-fusion model the arms separate: canonical signalling supports leukaemia stem cells, while driving the non-canonical arm suppresses the leukaemia - so 'the NF-kB pathway' is not one therapeutic direction. Xiu Y et al. 2018
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In MLL-AF9 leukaemia stem cells, stabilisation of NIK reduced the expression and nuclear localisation of RelA protein, and the decrease in nuclear RelA was attributed at least in part to NIK-induced upregulation of the canonical pathway inhibitors Nfkbia/IkBa and Tnfaip3/A20, which form a negative-feedback control of canonical NF-kB signalling.
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. · Xiu Y, Dong Q, Li Q, Li F, Borcherding N, Zhang W, Boyce B, Xue HH, Zhao C · Cell Reports 2018What this evidence cannot show
Nfkbia upregulation is an RNA-seq and western observation in NIK-stabilised mouse LSCs, and the attribution of falling nuclear RelA to it is the authors' interpretation ('at least partially due to'), not a rescue experiment - no IkBa knockdown was performed to test it. Mouse MLL-AF9 only. Full text read this session (PMC5810947).
Evidence that argues against this (1)
- The causal chain implied here does not hold on its own terms: overexpressing RelA failed to restore colony formation or reverse the delay in leukaemogenesis caused by NIK stabilisation. So reduced canonical output, however produced, is not sufficient to explain the anti-leukaemic effect, and the RelB target programme (Dnmt3a up, Mef2c down) carries part of it. Xiu Y et al. 2018
- E3strong 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 (NFKBIA OR "IkappaB alpha"[tiab] OR "IkBalpha"[tiab] OR "I kappa B alpha"[tiab]) returns 2 PubMed records. One is an emodin/RAW 264.7 inflammation study, off beat. The other is the non-leukaemic MLL1/NF-kB recruitment paper. Title-checked count in KMT2A-rearranged leukaemia: 0.
PubMed E-utilities esearch, db=pubmed, run 2026-09-20 · NCBI · PubMed 2026What this evidence cannot show
querytranslation was read; PubMed expanded NFKBIA to its supplementary-concept term. The alias MAD-3 and the spelling 'I-kappaB-alpha' were not searched separately. As with IKBKG, a symbol-keyed count misses papers that frame at pathway level, so this bounds the absence of IkBa-framed work rather than of all work touching it.
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
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt reviewed human record P25963 (IKBA_HUMAN) has primary gene name NFKBIA and length 317 aa; gene_exact:NFKBIA AND organism_id:9606 AND reviewed:true returned exactly one row and gene_primary read back as NFKBIA.
UniProtKB entry P25963 (IKBA_HUMAN), NF-kappa-B inhibitor alpha · UniProt Consortium · UniProt 2026What this evidence cannot show
Resolved 2026-09-20 with gene_primary requested and all rows read. NFKBIB (Q15653, 356 aa) and NFKBIE (O00221, 500 aa) were resolved the same way and return zero relevant records in this disease; they are recorded as bounded absences in ana-nfkb-upstream-enumeration-and-bounded-absences rather than given entries.
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
phosphorylates IkB-alpha and triggers its proteasomal degradation
sequesters RELA:p50 in the cytoplasm until degraded
NIK stabilisation upregulates Nfkbia and Tnfaip3, lowering nuclear RelA
bortezomib is called an NF-kB inhibitor because it blocks IkBa degradation; the label is unsafe here