Oncofusion

start / graph / gene-wt1

Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q152-aff1-only-recurrent-core

WT1 - Wilms tumour 1, leukaemia antigen and MRD marker, and the widest-margin promoter in the Q152 AFF1-only core

also called WT-1 · Wilms tumor protein · WT33

WT1 is a gene that is normally quiet in blood cells but is switched on in many leukaemias, which is why it is used both to track residual disease and as a target for immune therapies. In this project's occupancy data its switch shows the cleanest separation of any gene between the KMT2A::AFF1 patients and the others - but the separation is not statistically more than chance for a set of seventeen.

The same thing, for a scientist

WT1 (P19544, 449 aa) is a zinc-finger transcription factor, a widely used minimal-residual-disease marker in acute leukaemia and one of the most-pursued leukaemia immunotherapy antigens. It is named here because its 2 kb promoter is occupied in 4 of 8 KMT2A::AFF1 samples of GSE252378 at 3.18-5.14x with the highest non-AFF1 value 1.47x - a separation margin of 2.17, the widest of the 17-gene AFF1-only recurrent core. Q152's headline result is that the core as a whole is within the label-permutation null, so this occupancy is recorded as an observation and not as a target call. WT1 already appears in 23 node files of this graph, always as a co-mutation or as an antigen, never as a KMT2A-fusion target.

Go deeper
Why WT1 needs an entry regardless of this beat's verdict

WT1 is named in 23 entries of this corpus - in NUP98-NSD1 comparative entries, in menin-inhibitor resistance co-mutation entries, in MPAL mechanism entries - and has had no entry of its own. It is an active immunotherapy target, which makes every statement about it intervention-adjacent and therefore subject to the bite-back requirement.

The occupancy observation, stated at its real strength

4 of 8 AFF1 samples (p179, p247, p279, p454 - four distinct patients), occupied calls 3.18x, and up to 5.14x; highest non-AFF1 min-of-replicates 1.47x in p214; no non-AFF1 sample above 1.5x 2. That is the widest margin in the core. It is also, on Q152's own permutation null, a 4-of-8 pattern that a random eight-sample arm produces routinely. Both statements are true and the second is the one that governs.

The prognostic literature does not point one way

WT1 expression is used as a prognostic and MRD marker in acute leukaemia, but the direction is not settled in paediatric ALL: a 40-patient paediatric ALL series found higher relapse and death rates and poorer MRD clearance in the WT1-negative group, the opposite of the usual reading 3. That is a small single-centre study and is cited here as counter-evidence to a simple 'WT1 high is bad' inference, not as a finding.

Facts and figures
uniprotP19544
length AA449
gene symbolWT1
hgnc symbolWT1
chromosome11p13
promoter hg38chr11:32,434,539-32,436,539 (TSS 32,435,539, minus strand, NM_000378)
shown for fusionNO - nobody has published a KMT2A-fusion occupancy or knockdown experiment on WT1 that this beat could find. WT1 appears in this graph as a menin-inhibitor resistance co-mutation and as a NUP98-NSD1 comparative feature, never as a KMT2A-fusion target.
clinical roleminimal-residual-disease marker; immunotherapy antigen (vaccine and TCR/CAR approaches)
relationship to existing entriesNamed by beat Q152 because its promoter sits in the 17-gene AFF1-only recurrent core of GSE252378. Q152's headline result is that that core is NOT more recurrence than a label permutation gives (p = 0.11), so this entry does NOT claim the gene is a KMT2A::AFF1 target on the strength of that occupancy. The entry exists because the gene is real biology in this disease and had no entry. WT1 is named in 23 existing node files as a co-mutation or antigen and had no entry of its own; this entry is the gene entry, and it does not assert a fusion-target relationship.
measurements
[
  {
    "quantity": "n_aff1_samples_occupied",
    "subject": "WT1 2 kb promoter in the KMT2A::AFF1 arm of GSE252378",
    "value": 4,
    "units": "samples of 8",
    "n": 27,
    "universe": "27 GSE252378 KMT2A-fusion samples, two-antibody 2.0x within-sample share plus per-library width-matched floor",
    "null": 2.73,
    "note": "p179, p247, p279, p454; occupied calls 3.18-5.14x; 0 of 19 non-AFF1, highest non-AFF1 1.47x (p214), separation margin 2.17. Null 2.73 is q151's per-promoter expectation across 27 samples. Q152 shows a 3-of-8 count at this pass rate is within the chance range."
  }
]
How this could bite us back
  • WT1 is expressed in normal renal podocytes, gonad and a subset of CD34+ haematopoietic progenitors, so a WT1-directed T-cell or antibody therapy carries on-target, off-tumour risk in kidney and in the stem-cell compartment that must be repopulated after treatment.
  • WT1 antigen-directed therapy is HLA-restricted, so efficacy is confined to patients with the matching allele and escape by HLA loss or downregulation is a documented route in leukaemia.
  • If WT1 promoter occupancy by the fusion is real, a menin inhibitor that removes the fusion would lower WT1 expression and could reduce the very antigen a concurrent WT1-directed immunotherapy depends on - a direct combination antagonism this graph has not tested.
  • WT1 has both tumour-suppressor and oncogene behaviour depending on isoform and context, so knocking it down as a therapy is not obviously safe even where it is expressed.
Still open
  1. Is WT1 transcript elevated in the four GSE252378 KMT2A::AFF1 patients whose promoters are occupied, and flat in the four that are not? A paired RNA readout exists for some of these samples and was not joined here.
  2. Has any WT1-directed immunotherapy trial reported a KMT2A-rearranged subgroup? Not searched in this beat.
  3. Does WT1 promoter occupancy move under a menin inhibitor in any deposited KMT2A-rearranged dataset?
Every source behind this entry (3)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    WT1 is a reviewed human UniProt entry, accession P19544, 449 residues, Wilms tumour protein.

    UniProtKB P19544 - Wilms tumor protein (Homo sapiens), reviewed · UniProt Consortium · UniProtKB/Swiss-Prot 2026
    What this evidence cannot show

    gene_exact:WT1 returns a single reviewed human record; data/symbol-collisions.json has no WT1 row (checked, 211 rows). The canonical isoform length varies with the +KTS/-KTS and exon 5 splice forms, which the single length_aa does not capture.

    Evidence that argues against this (1)
    • WT1 has at least four major isoforms from alternative splicing at exon 5 and the KTS insertion, with opposing transcriptional activities; a single canonical length and accession cannot represent the molecule that matters functionally or as an antigen. UniProt Consortium 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In GSE252378 the WT1 2 kb promoter (hg38 chr11:32,434,539-32,436,539, minus-strand refGene TSS 32,435,539, NM_000378) is occupied in 4 of 8 KMT2A::AFF1 samples (p179, p247, p279, p454, four distinct patients) at min-of-replicate within-sample shares of 3.18-5.14x and in 0 of 19 non-AFF1 samples, with the highest non-AFF1 value 1.47x in p214 and no non-AFF1 sample above 1.5x - a separation margin of 2.17, the widest of the 17 core promoters.

    Q152 per-core-gene occupancy and separation margins over GSE252378 · Iqbal Lab oncofusion knowledge graph, beat Q152 · this project 2026
    What this evidence cannot show

    The same beat's permutation null shows that a 4-of-8 AFF1-exclusive pattern is within the chance range for this rule, so this is an observation about four patients and not a target call. No non-AFF1 partner family is represented by more than four samples, so partner-level absence is weakly powered.

    Evidence that argues against this (1)
    • The comparator's highest reading (1.47x in p214) is only 1.5-fold below the weakest AFF1 call at a rule whose own threshold is 2.0x, and the same beat's permutation shows 4-of-8 exclusivity is common. Naming WT1 the widest-margin member is a statement about a ranking with no null on it. Iqbal Lab oncofusion knowledge graph et al. 2026
  3. E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    In a 40-patient series of Egyptian children with newly diagnosed ALL, 22 (55%) were WT1-positive by RT-PCR, and the WT1-NEGATIVE group had significantly higher relapse and death rates, lower complete remission, disease-free and overall survival, and significantly worse MRD clearance (89% of WT1-positive versus 33% of WT1-negative attained MRD negativity, p = 0.006).

    Prognostic Impact of WT-1 Gene Expression in Egyptian Children with Acute Lymphoblastic Leukemia · Hagag AA, Badraia IM, Hassan SM, Abd El-Lateef AE · Mediterr J Hematol Infect Dis 8:e2016008 2016
    PMID 26740869DOI
    What this evidence cannot show

    n = 40, single centre, RT-PCR positivity rather than quantitative level, no KMT2A-rearranged subgroup and no infant subgroup. Cited as counter-evidence to a directional reading of WT1 expression, not as a prognostic finding.

    Evidence that argues against this (1)
    • The direction in this 40-patient series is opposite to the usual reading of WT1 as an adverse marker, and the study is small, single-centre and uses RT-PCR positivity rather than a quantitative level. It is cited to show the direction is unsettled, and it is itself weak evidence for either direction. Hagag AA et al. 2016
Connected to