RELB — the NF-kB subunit that SUPPRESSES MLL-AF9 leukaemia, with a direct ChIP target list and a genetic rescue, which makes it the best-evidenced anti-leukaemic node 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.

• The therapeutic reading of this entry is 'activate the non-canonical arm', and the only tool for that also impairs normal haematopoietic stem and progenitor self-renewal, which the authors state and treat as the key obstacle.
• RelB drives medullary thymic epithelial development and secondary lymphoid organogenesis. Chronically activating it in an infant is not a neutral act.
• A subunit whose disease direction is established in one mouse fusion by one laboratory should not be carried into KMT2A::AFF1 B-ALL without a lymphoid experiment; the graph has been burned before by inheriting a myeloid narrative.
• RelB and RelA cross-repress, so any intervention that raises RelB lowers RELA and vice versa. A combination that targets both arms may cancel itself.
• RELB is anti-leukaemic in this entry's own evidence, so the intervention that follows is AGONISM, not inhibition - and there is no way to agonise a transcription factor pharmacologically today. Any near-term attempt would act on the upstream non-canonical arm (NIK, p100 processing), which is not RELB-specific.
• Losing RelB in mice causes multiorgan inflammation, loss of thymic dendritic cells and impaired cellular immunity (PMID 7834753). If a drug in this disease inhibits the non-canonical arm as an off-target, it removes an immune compartment in a patient already immunosuppressed by chemotherapy.
• RELB, RELA and REL are 579, 551 and 619 aa (UniProt Q01201, Q04206, Q04864, fetched 2026-09-21). The length margins are 28 and 40 residues, so a swap is mechanically catchable - but RELB points the OPPOSITE way to RELA in this disease, so a subunit confusion here does not blur a claim, it inverts a therapeutic direction, and the tool compounds for the pathway are arm-level rather than subunit-level.

1. Is TIFAB a direct RelB ChIP target or not? One paper reports RelB does not bind the Tifab promoter and a later paper from the same group calls TIFAB a direct RelB target. Both cannot be read at face value and the graph should not pretend otherwise.
2. Does RelB have the same direction in KMT2A-rearranged B-ALL? A biphenotypic line paper points the other way in a lymphoid-morphology context, and infant B-ALL is the index disease.
3. What is endogenous RelB doing in patient blasts? Every result here is from overexpression or from an engineered non-degradable NIK.
4. If RelB is protective and RELA is permissive, does a menin inhibitor shift the balance? Menin binds NFKB2 as well as RELA, so the released species may not be the one the resistance hypothesis assumes.
5. What is RELB doing at the centrosome? UniProt annotates a centrosomal pool at ECO:0000269 and no NF-kB model accounts for it; if it is real it is a function that any upstream non-canonical inhibitor would also remove.
6. Is the myeloid restraint RelB exerts in the normal mouse the SAME mechanism as the MLL-AF9 suppression this entry records, or two different things pointing the same way? Nobody has tested the knockout's direct ChIP targets against the leukaemia's.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   In MLL-AF9 AML, overexpression of RelB significantly repressed and overexpression of RelA significantly accelerated leukaemia; NIK stabilisation upregulated NfkB2 and Relb without significantly altering canonical components Nfkb1, Rela or Rel, increased nuclear RelB and p52, and reduced RelA expression and nuclear localisation. RelB binds directly to the Mef2c promoter and to a Dnmt3a promoter in front of exon 7, but not to the Tifab promoter; overexpression of DNMT3A suppressed and of MEF2C enhanced AML development. Knockdown of Relb partially restored NIK's anti-leukaemic effect, whereas neither Dnmt3a knockdown nor MEF2C overexpression restored the NIK-induced delay. The suppression was not due to enhanced differentiation and apoptosis was only modestly increased; GSEA showed suppression of genes controlled by Hoxa9 and Meis1 without significant change in Hoxa9 or Meis1 expression themselves.

   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 2018
   PMID 29320732DOI
   ▸What this evidence cannot show

   Entirely mouse MLL-AF9, driven by a non-degradable NIK mutant (NIK-deltaT3) rather than by a drug, with RelB manipulated by overexpression and shRNA. Overexpression assigns sufficiency, not physiological role: endogenous RelB has never been measured in a KMT2A-rearranged patient sample in this literature. The 'broad anti-human myeloid leukaemia role' claim rests on a supplementary figure. No B-lymphoid model and no KMT2A::AFF1 experiment. Full text read this session (PMC5810947).

   ▸Evidence that argues against this (1)

   • RelB is not uniformly tumour-suppressive across leukaemia. In a biphenotypic B-myelomonocytic line with lymphoblastic morphology, RelB expression was shown to repress the tumour suppressor DAPK1 - a pro-tumour direction. The authors of the MLL-AF9 work cite this themselves as the counter-case and note that no functional studies had been reported either way before theirs. Xiu Y et al. 2018
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Deletion of RelB prevents the inhibitory effect of NIK stabilisation in MLL-AF9 AML. Mechanistically RelB suppresses its direct target TIFAB, which is upregulated in human AML and correlates negatively with patient survival; forced TIFAB expression reverses NIK-induced impairment of AML development through downregulation of RelB and upregulation of HOXA9, and forced HOXA9 expression also largely releases NIK's inhibition via downregulation of RelB and upregulation of RelA.

   TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9. · Zhao J, Xiu Y, ... Zhao C · iScience 2021
   PMID 34877491DOI
   ▸What this evidence cannot show

   Abstract read; full text not retrieved. Same laboratory and same mouse MLL-AF9 model as E1, so this is extension rather than independent replication. Note the apparent conflict with E1, where RelB ChIP was reported as NOT binding the Tifab promoter while this paper calls TIFAB a direct RelB target; the two can be reconciled only by reading both sets of ChIP primers, which was not possible from the abstract. Flagged as an open question rather than resolved.

   ▸Evidence that argues against this (1)

   • This entry's own beat carries a direct tension with this claim: a chromatin immunoprecipitation in the earlier MLL-AF9 study found RelB binding the Mef2c and Dnmt3a promoters but NOT the Tifab promoter. 'RelB suppresses its DIRECT target TIFAB' and 'RelB does not bind the Tifab promoter' cannot both be right as stated, and neither paper cites the other on the point. Xiu Y et al. 2018
3. 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 (RELB OR "RelB"[tiab]) returns 4 PubMed records: the NIK/MLL-AF9 paper, the two TIFAB papers from the same group, and an Elf1 innate-immunity paper. All the KMT2A-relevant RELB literature is from one laboratory and one mouse model.

   PubMed E-utilities esearch, db=pubmed, run 2026-09-20 · NCBI · PubMed 2026
   ▸What this evidence cannot show

   querytranslation was read. The alias I-Rel was not searched separately; it is a short word-like alias of exactly the kind the brief warns inflates counts, so it was deliberately excluded rather than overlooked.

   ▸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
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt reviewed human record Q01201 (RELB_HUMAN) has primary gene name RELB and length 579 aa; gene_exact:RELB AND organism_id:9606 AND reviewed:true returned exactly one row and gene_primary read back as RELB.

   UniProtKB entry Q01201 (RELB_HUMAN), Transcription factor RelB · UniProt Consortium · UniProt 2026
   ▸What 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
5. E_q71_ct1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   In MICE, germline disruption of relB removes RelB protein and dramatically reduces constitutive kappa-B-binding activity in THYMUS AND SPLEEN, and produces multifocal mixed inflammatory infiltration in several organs, MYELOID HYPERPLASIA, splenomegaly due to EXTRAMEDULLARY HAEMATOPOIESIS, a REDUCED POPULATION OF THYMIC DENDRITIC CELLS and impaired cellular immunity - and the authors state the absence cannot be functionally compensated by any other NF-kB/Rel family member.

   Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. · Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R · Cell 1995
   PMID 7834753DOI
   ▸What this evidence cannot show

   Abstract read in full; full text not read. MURINE germline knockout, normal immune development - not leukaemia, not human, not KMT2A-rearranged, and myeloid/dendritic rather than B-lineage (brief rule 73). A germline knockout in a mouse with multiorgan inflammation cannot separate cell-intrinsic haematopoietic effects from consequences of the inflammatory phenotype; the myeloid hyperplasia and extramedullary haematopoiesis are compatible with either. 'Non-redundant' is the authors' inference from a single knockout, not a compound-knockout result.

   ▸Evidence that argues against this (1)

   • The direction is consistent across systems in a way that argues against a fusion-specific reading. This entry already records RELB as SUPPRESSING MLL-AF9 leukaemia with a direct ChIP target list and a genetic rescue; the knockout mouse shows that losing RelB expands the myeloid compartment in an animal with NO fusion at all. So myeloid restraint by RelB is a property of normal haematopoiesis that the leukaemia result recapitulates, rather than something the fusion creates. This project's own scan agrees that RELB is not a dependency: Chronos -0.0154 in the KMT2A-rearranged arm and -0.0790 in other leukaemias, pan-essentiality -0.0926 - all within noise of zero, so rank 15,662 of 17,728 describes a non-dependency and should not be read as a selectivity measurement. Barlow C et al. 1996

• ← regulatesMAP3K14 (NIK) — the one node in this pathway where ACTIVATION, not inhibition, is the proposed therapy, and the one that also damages normal stem cells

  NIK stabilisation upregulates RelB and its nuclear localisation

• inhibits →KMT2A-rearranged acute myeloid leukaemia in children and infants

  RelB overexpression represses MLL-AF9 AML; RelB deletion abolishes NIK's protection

• inhibits →RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin

  RelB overexpression represses RelA protein; the two arms cross-repress

• inhibits →TIFAB — a 161-residue NF-kB adaptor-layer protein with TWO direct KMT2A-fusion papers, which is more disease-specific evidence than any receptor or TRAF in this beat has

  RelB suppresses TIFAB (but the 2018 ChIP found no RelB binding at the Tifab promoter)

• ← inhibitsTIFAB — a 161-residue NF-kB adaptor-layer protein with TWO direct KMT2A-fusion papers, which is more disease-specific evidence than any receptor or TRAF in this beat has

  forced TIFAB downregulates RelB and reverses NIK's anti-leukaemic effect

• ← bindsNFKB2 (p100/p52) — menin binds the non-canonical subunit too, and activating that arm SUPPRESSES MLL-AF9 leukaemia

  p52 partners RelB as the non-canonical dimer

• ← related toCanonical versus non-canonical NF-kB in KMT2A-rearranged leukaemia — the two arms have opposite signs, and the two papers usually read as contradicting each other actually agree

  the non-canonical effector, with the opposite sign to RELA

• regulates →Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for

  REQUIRED IN (imperfect node match): relB-null mice have a reduced population of THYMIC dendritic cells and impaired cellular immunity; this graph has no thymic or conventional DC node, so the edge is drawn weakly and the discrepancy is stated (murine germline knockout; PMID 7834753)

• regulates →Granulocyte-monocyte progenitor (GMP) — the committed cell an MLL fusion can turn back into a stem cell

  RESTRAINS: relB-null mice show myeloid hyperplasia and splenomegaly from extramedullary haematopoiesis, so RelB limits the myeloid compartment in an animal with no fusion - the same direction as this entry's MLL-AF9 suppression result (murine; PMID 7834753)

• related to →The soluble-nucleoplasm versus chromatin-bound axis - the one localisation readout that keeps a size dimension, and nobody has run it on a KMT2A fusion

  RELB's compartment is stimulus-dependent (cytoplasmic RelB/p100 until NIK-driven processing releases RelB/p52 to the nucleus) and UniProt adds an experimental centrosomal pool; no subnuclear measurement exists and a soluble-versus-chromatin fractionation is the missing one

• expressed in →Conventional (myeloid-related) dendritic cell - the DC lineage RELB actually builds, and the thymic part of that phenotype is architecture rather than a cell-intrinsic requirement

  RESIDENCY: relB transcripts are detected in the thymic medulla, splenic PALS and lymph-node deep cortex, and double immunofluorescence identifies interdigitating dendritic cells as the RelB-expressing cell; RelB mRNA is strong in CD8alpha-negative DEC-205-negative DC and weak in CD8alpha-positive DC

• regulates →Conventional (myeloid-related) dendritic cell - the DC lineage RELB actually builds, and the thymic part of that phenotype is architecture rather than a cell-intrinsic requirement

  REQUIREMENT, separate from the residency edge: the splenic CD8alpha-negative DEC-205-negative DC deficiency in RelB-null mice is stem-cell-intrinsic by bone-marrow chimera, while CD8alpha-positive DC are present and functional

• ← regulatesTRAF2 - a cytoplasmic NF-kB brake reported as an AFF4 two-hybrid hit, 97 partners in the screen that found it, and the live instance of the brief's own accession trap

  TRAF2 with TRAF3 and the cIAPs degrades NIK, restraining the NFKB2/RELB non-canonical arm; TRAF2 loss releases it

• ← refutesIs TIFAB a direct RelB target? Two papers in the same MLL-AF9 system answer differently

  THE DIRECTNESS CLAIM IS UNSETTLED: 'RelB suppresses its direct target TIFAB' is the 2021 abstract's wording, and the 2018 companion study names Dnmt3a and Mef2c instead.