Oncofusion

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Proteinmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q49-metabolism

HNF4A - a liver and pancreas nuclear receptor acting as the metabolic effector of TIFAB in KMT2A::MLLT3 AML, on a single paper

also called HNF4A · HNF4 · NR2A1 · TCF14 · hepatocyte nuclear factor 4-alpha · P41235

HNF4A is a switch that normally runs the metabolism of liver and pancreas cells, and it turns out to be switched on in a mouse model of KMT2A-rearranged myeloid leukaemia, where it restores the leukaemia cells' ability to take up sugar and run their mitochondria. It is an odd gene to find in blood cancer, which is exactly why it is worth an entry.

The same thing, for a scientist

HNF4A (UniProt P41235, 474 aa, primary gene name read back 2026-09-20) is a nuclear receptor (NR2A1) that governs hepatic and pancreatic metabolic gene programmes and is the gene mutated in MODY1. It enters this graph as the named metabolic effector in a single study: in KMT2A::MLLT3-induced AML, Tifab deletion impaired leukaemia stem/progenitor cell engraftment, glucose uptake and mitochondrial function and downregulated MYC, HOXA9/MEIS1, mTORC1 signalling, glycolysis and oxidative phosphorylation genes; HNF4A was identified as a key TIFAB target regulated through TIFAB's inhibition of the NF-kB component RelB, which suppresses Hnf4a in leukaemia cells; **HNF4A rescued the metabolic defects of Tifab deletion**, and Hnf4a knockdown attenuated TIFAB-mediated enhancement of LSPC function [E1]. This graph already carries `gene-tifab`, which records this paper; HNF4A gets its own entry because the PI's granularity rule says the effector inside a mechanism is its own thing, and because HNF4A was named in exactly one entry of this graph on 2026-09-20 with no entry of its own. **The confidence here is deliberately capped at moderate**: one paper, one laboratory, one mouse fusion model, and a rescue experiment as the load-bearing evidence.

What it looks like
loading AF-P41235-F1…
AlphaFold AF-P41235-F1 ↗
colourshape

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.

very high (90+)confident (70–90)low (50–70)very low (<50)
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.

Go deeper
Why an endoderm nuclear receptor in a myeloid leukaemia is interesting rather than suspicious

HNF4A is not expressed in normal haematopoiesis in any ordinary account of it. A leukaemia that switches on a hepatocyte metabolic master regulator is doing something more specific than 'upregulating metabolism' - it is borrowing a whole tissue's metabolic wiring. That is a mechanistically distinctive claim and it generates a cheap test: HNF4A protein or its target genes should be detectable in KMT2A-rearranged patient blasts, and this is checkable in existing public expression data without new experiments.

It is also the kind of claim that is easy to produce artefactually from bulk transcriptomics of marrow that contains non-haematopoietic contamination, or from a signature-scoring method. The cited study's rescue and knockdown experiments are what move it past that objection, and those are the parts of the abstract this entry leans on 1.

What this adds to gene-tifab, and what it does not

gene-tifab records the TIFAB phenotype and, correctly, flags that TIFAB's effect has now been attributed to three different downstream routes across three papers from the same laboratory - HOXA9, USP15/p53, and HNF4A. Three mechanisms for one gene is a warning, not a synthesis, and that warning applies to this entry too: HNF4A is the third proposed route, not an agreed one.

What this entry adds is the metabolic specifics, which gene-tifab states but does not develop: the measured phenotypes are glucose uptake and mitochondrial function, and the downregulated programmes are mTORC1, glycolysis and OXPHOS together 1. Note that glycolysis and OXPHOS move in the same direction here. That is worth flagging, because much of this beat's literature treats them as a see-saw, and in this model they are not.

Facts and figures
uniprotP41235
length AA474
alphafold IDAF-P41235-F1
receptor familynuclear receptor NR2A1; paralogue HNF4G (NR2A2)
resolution notegene_exact:HNF4A AND organism_id:9606 AND reviewed:true returned 1 reviewed row on 2026-09-20; gene_primary read back as HNF4A; length 474 aa asserted. Hazards noted: synonym TCF14 collides visually with the E-protein TCF family; 'HNF4' unqualified is ambiguous with HNF4G.
role in beatmetabolic effector downstream of TIFAB and RelB in KMT2A::MLLT3 AML; rescues glucose uptake and mitochondrial function
programmes moved togethermTORC1, glycolysis AND oxidative phosphorylation all fall on Tifab deletion - glycolysis and OXPHOS are not reciprocal in this model
evidence lineagemouse KMT2A::MLLT3 only; no human, lymphoid or infant data
replication statussingle paper, single laboratory; no independent replication found 2026-09-20
phenotypes measured
[
  "glucose uptake",
  "mitochondrial function",
  "LSPC engraftment"
]
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": 0.0789,
  "chronos_mean_other_leukaemia": 0.0409,
  "difference": 0.038,
  "pan_essentiality_all_lines": 0.0278,
  "selectivity_rank": 13705,
  "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."
}
How this could bite us back
  • HNF4A is required for normal liver and pancreatic beta-cell function, and HNF4A loss-of-function causes MODY1 with neonatal hyperinsulinism. Systemic HNF4A antagonism in an infant risks a metabolic endocrine phenotype that is well characterised and serious.
  • The evidence is a single mouse model from a single laboratory whose own earlier ChIP is in tension with the regulatory chain proposed here. Building a programme on it without independent replication would repeat a failure mode this graph has already logged.
  • The upstream node is NF-kB. Targeting HNF4A to remove a metabolic advantage leaves the RelB axis free, and RelB manipulation has documented escape routes through HOXA9 in this exact disease.
Still open
  1. Is HNF4A actually expressed in human KMT2A-rearranged blasts? This is answerable today from public expression data and would either promote or retire this entry in an afternoon.
  2. Why do glycolysis and OXPHOS move together here when the rest of this beat's literature treats them as reciprocal? If both fall with one perturbation, the phenotype may be an LSPC-quantity effect rather than a metabolic-rewiring effect.
  3. TIFAB now has three proposed downstream routes from one laboratory. Which of HOXA9, USP15/p53 and HNF4A carries the phenotype, and has any of them been tested with the other two controlled?
  4. Is HNF4A druggable in this context? Nuclear receptors are historically tractable, and an antagonist would be a fast test of whether the metabolic arm is the arm that matters.
Every source behind this entry (2)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    TIFAB, an inhibitor of NF-kB signalling, enhances KMT2A::MLLT3-induced AML; Tifab deletion impairs leukaemia stem/progenitor cell engraftment, glucose uptake and mitochondrial function and downregulates MYC, HOXA9/MEIS1, mTORC1 signalling, glycolysis and oxidative phosphorylation genes; HNF4A was identified as a key TIFAB target regulated through inhibition of the NF-kB component RelB, which suppresses Hnf4a in leukaemia cells; HNF4A rescues the metabolic defects of Tifab deletion and Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function.

    PMID 39626355DOI
    What this evidence cannot show

    Abstract read this session; full text not retrieved, so the HNF4A expression measurements, the rescue construct and the knockdown efficiency were not checked. Mouse KMT2A::MLLT3 model; no human patient data and no lymphoid or infant data are claimed by the abstract. Single paper, single laboratory: this is the third distinct downstream route the same group has proposed for TIFAB across three papers (HOXA9, USP15/p53, HNF4A), which is a sign the mechanism is not settled rather than that it is now resolved. The mechanism is a double negative - TIFAB inhibits RelB, RelB suppresses Hnf4a - and double-negative regulatory chains are the ones most easily inverted by a reagent artefact. HNF4A is an endoderm nuclear receptor whose expression in haematopoietic cells is not independently established here. Bounded absence: a Europe PMC sweep on 2026-09-20 found no independent replication of the HNF4A arm in KMT2A-rearranged leukaemia.

    Evidence that argues against this (1)
    • The same laboratory's earlier MLL-AF9 work reports a chromatin immunoprecipitation in which RelB binds the Mef2c and Dnmt3a promoters but NOT the Tifab promoter, which is in tension with the later framing of TIFAB and RelB as a direct regulatory pair. This graph records the discrepancy as unresolved in gene-tifab, and it bears on the credibility of the RelB-Hnf4a step as well. Xiu Y et al. 2018
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProt reviewed human record P41235 (HNF4A_HUMAN) has primary gene name HNF4A, gene synonyms HNF4, NR2A1 and TCF14, length 474 aa, and recommended protein name 'Hepatocyte nuclear factor 4-alpha' with alternative name 'Nuclear receptor subfamily 2 group A member 1'.

    What this evidence cannot show

    Resolved 2026-09-20 with gene_exact:HNF4A AND organism_id:9606 AND reviewed:true; exactly one reviewed row and gene_primary read back as HNF4A. Two identifier hazards recorded: the synonym TCF14 collides visually with the unrelated TCF3/TCF4/TCF12 E-protein family that this disease's literature is full of, and the paralogue HNF4G (NR2A2) is a genuine second gene, so 'HNF4' without a letter is ambiguous. The study cited here writes HNF4A and Hnf4a throughout.

    Evidence that argues against this (1)
    • A reviewed record establishes the canonical human sequence and symbol. The cited experiments are in mouse, so the human accession asserted here is the orthologue of the protein actually manipulated, not the protein manipulated; nothing in the study establishes HNF4A protein in human KMT2A-rearranged blasts. Wang Y et al. 2025
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