Oncofusion

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Geneweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q84-pan-fusion-core

TRIM28 / KAP1 / TIF1beta (Q13263) - the KRAB-ZFP corepressor scaffold in the pan-MLL-fusion core, with the weakest index-fusion p-value but a leukaemic role in another fusion family

also called TRIM28 · KAP1 · KAP-1 · TIF1B · TIF1beta · RNF96 · transcription intermediary factor 1-beta

TRIM28 (also called KAP1 or TIF1-beta) is the platform that KRAB zinc-finger proteins use to switch genes off, by recruiting the enzyme that writes the silencing mark H3K9me3. It co-purifies with all seven MLL fusions, and in a different leukaemia fusion - BCR::ABL1 - deleting it slows the disease down.

The same thing, for a scientist

TRIM28 (Q13263, 835 aa) is the universal corepressor for the KRAB zinc-finger protein family; it binds SETDB1, whose H3K9 methylation recruits HP1 and silences euchromatic genes. In Skucha 2018 it co-purified with all seven MLL fusions, but the MLL-AF4 (= KMT2A::AFF1) call is p = 0.129 with 3|2 spectra - the second weakest index-fusion measurement in this beat - and even MLL-AF1p is 0.078. Only MLL-ENL (0.00347, 9|11), MLL-GAS7 (0.00592, 14|10) and MLL-AF9 (0.0109, 9|8) fall below 0.05. The independent leukaemia evidence is real but belongs to another fusion family: Tif1b deletion in a BCR::ABL1 conditional knock-in mouse inhibited myeloid leukaemia progression, extended survival and sensitised the leukaemic cells to dasatinib, acting through FOSL1. TRIM28 is mentioned in ZERO node files in this graph before this entry.

Go deeper
The Skucha row

7 of 7 fusions, but weakly at the index bait. MLL-AF1p 0.078 (3|3), MLL-AF4 0.129 (3|2), MLL-AF9 0.0109 (9|8), MLL-CBP 0.0364 (4|4), MLL-EEN 0.0298 (9|7), MLL-ENL 0.00347 (9|11), MLL-GAS7 0.00592 (14|10); negative control 0|0 1. Two of the seven per-bait p-values are themselves above 0.05, so 'binds all seven' here means 'in the top 300 of all seven', which is a materially weaker statement.

What TRIM28 does

KAP-1 is the corepressor for the KRAB zinc-finger superfamily and binds SETDB1, an H3K9-specific methyltransferase whose product is sufficient to enhance HP1 binding to the histone H3 tail; that chain is how KRAB-ZFPs silence euchromatic genes 2. The relevance to a KMT2A fusion is not obvious - the fusion's canonical output is activating - which is exactly why this row needs an orthogonal test rather than a narrative.

Analogous biology in another fusion family

In a BCR::ABL1 conditional knock-in mouse, deletion of Tif1b inhibited myeloid leukaemia progression and lengthened survival, sensitised the leukaemic cells to dasatinib, and reduced chromatin accessibility at FOSL1 motifs in BCR::ABL1 stem cells; TIF1beta bound the FOSL1 promoter directly in human BCR::ABL1 cells 3. TIF1beta expression is also raised in CML blast crisis and AML. This is a documented leukaemic dependency on TRIM28 - in a different fusion, a different lineage and mostly in mouse - and it is recorded here as analogous biology, which is one of this project's standing priorities, not as evidence about KMT2A::AFF1.

Facts and figures
uniprotQ13263
length AA835
accession resolutionResolved live 2026-09-21: gene_exact:TRIM28 AND organism_id:9606 AND reviewed:true returns exactly one row, gene_primary TRIM28, Q13263, TIF1B_HUMAN, 835 aa, synonyms KAP1 RNF96 TIF1B. Matches Skucha's table. The entry name TIF1B_HUMAN does not contain the string TRIM28, which is the failure mode that makes a correct record look like a failed lookup - the primary gene name is what settles it.
localizationNucleus
subnuclear localizationNot assigned to a named subnuclear body; heterochromatin-associated through HP1 and SETDB1.
localization evidenceUniProt Q13263, fetched 2026-09-21: a single location comment, Nucleus, carrying EIGHT independent ECO:0000269 experimental citations - the best-evidenced nuclear call of the twelve proteins in this beat, and still no subnuclear resolution.
shown for fusionKMT2A::AFF1 (MLL-AF4) by co-purification only and at p = 0.129, plus the six other Skucha baits. Functionally shown for BCR::ABL1 in mouse - a different fusion family and lineage. NO independent experiment ties TRIM28 to any KMT2A fusion.
graph contextTRIM28 and KAP1 appear in ZERO node files in this graph before this entry (grep -rl over data/graph/nodes, 2026-09-21).
skucha 2018
{
  "bait": "MLL-AF4 (= KMT2A::AFF1)",
  "p_value": 0.129,
  "spectral_counts": "3|2",
  "n_fusions_of_seven": 7,
  "negative_control_counts": "0|0",
  "per_bait": {
    "MLL-AF1p": "0.078 (3|3)",
    "MLL-AF4": "0.129 (3|2)",
    "MLL-AF9": "0.0109 (9|8)",
    "MLL-CBP": "0.0364 (4|4)",
    "MLL-EEN": "0.0298 (9|7)",
    "MLL-ENL": "0.00347 (9|11)",
    "MLL-GAS7": "0.00592 (14|10)"
  },
  "index_bait_warning": "p = 0.129, the second weakest index-fusion call in this beat; MLL-AF1p is also above 0.05.",
  "source": "analyses/skucha-mll-fusion-interactome/results.json, re-derived from the cached MOESM4 xlsx on 2026-09-21"
}
cell types and states
[
  "Jurkat (human T-ALL) - AP-MS host, nuclear lysate",
  "mouse BCR::ABL1 conditional knock-in HSCs and leukaemic cells - Tif1b deletion delays leukaemia, sensitises to dasatinib",
  "human BCR::ABL1 cells - TIF1beta at the FOSL1 promoter",
  "human CML blast crisis and AML samples - elevated TIF1beta expression",
  "no KMT2A-rearranged cell of any kind"
]
bounded literature
{
  "query": "TRIM28[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab])",
  "querytranslation": "\"TRIM28\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract])",
  "count": 2,
  "on_topic_after_title_check": 0,
  "rejected": "PMID 37108449 (HMGXB4 targets Sleeping Beauty transposition to germinal stem cells) and PMID 28476430 (imprinted control regions, ZFP57 binding sites overlapping 'MLL1 morphemes' - a sequence-motif usage of MLL, not the protein).",
  "alias_query": "KAP1[tiab] AND (KMT2A[tiab] OR MLL[tiab]) returns 3, querytranslation \"KAP1\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract]); title-checked to 0 on topic (bovine imprinting control regions, a CDK9 review, and the same ZFP57 imprinting paper).",
  "names_tried": [
    "TRIM28",
    "KAP1"
  ],
  "date": "2026-09-21",
  "tool": "NCBI esearch db=pubmed",
  "positive_control": "the identical query shape with MEN1 returns 85",
  "bound": "Titles and abstracts only; supporting figures not searched. TIF1B and TIF1beta were not run as separate strings and could add records."
}
functionally screened in the source paper
{
  "_added": "king, cycle 48, 2026-09-21, after Q86 flagged that cycle-47 entries understate the record. Verified by me directly from the supplementary file, not from the paper's prose.",
  "screened": true,
  "library_symbol": "TRIM28",
  "shrnas_for_this_gene": 6,
  "design": "Supplementary Table 6 / MOESM5 is 768 data rows, 128 unique gene symbols, EXACTLY 6 shRNAs each -- counted with openpyxl on 2026-09-21. Negative-selection RNAi screen in MLL-AF9-expressing MOLM-13.",
  "what_this_DOES_establish": "Every one of the 128 conserved MLL-fusion interactors, this protein included, was functionally tested against an MLL fusion. An entry saying 'nothing in the paper validates this prey' is true of BINDING and understates the record.",
  "what_this_does_NOT_establish": "A per-gene result. Scores are presented as heatmaps (Fig. 2c/2d) and no per-gene depletion value is tabulated, so for any individual gene the outcome is measured-not-reported. It is also MLL-AF9 MOLM-13, a myeloid line, not the index fusion and not B-lineage.",
  "absence_class_for_the_per_gene_score": "measured-not-reported"
}
How this could bite us back
  • TRIM28 silences endogenous retroelements; depleting it de-represses them and triggers interferon responses, which in an infant on immunosuppressive chemotherapy is a specific and foreseeable harm.
  • The only leukaemia dependency evidence is in BCR::ABL1 mouse, where the therapeutic partner is a TKI that does not exist for this disease. Importing the strategy imports the wrong backbone.
  • TRIM28 is required for normal HSC maintenance in the same body of work that proposes it as a target, so the therapeutic index is unestablished.
Still open
  1. Does TRIM28 associate with KMT2A::AFF1 at all when measured with a method that is not rank-truncated? p = 0.129 with 3|2 spectra could be noise.
  2. Is SETDB1 in the Skucha 960-protein network? A TRIM28-SETDB1 pair would be a corepressor module rather than a lone scaffold.
  3. Does the BCR::ABL1 TIF1beta-FOSL1 axis have any counterpart in KMT2A-rearranged leukaemia, where AP-1 family activity is also described?
  4. Were TIF1B and TIF1beta ever searched as separate strings against the KMT2A literature? This beat ran TRIM28 and KAP1 only.
Every source behind this entry (3)
  1. E1weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    TRIM28 co-purified with all seven Strep-HA-tagged MLL fusions in isogenic Jurkat cells; the MLL-AF4 (= KMT2A::AFF1) call is p = 0.129 with 3|2 spectral counts, and two of the seven per-bait p-values (MLL-AF4 0.129, MLL-AF1p 0.078) are above 0.05.

    MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. · Skucha A, Ebner J, Schmoellerl J, Roth M, Eder T, Cesar-Razquin A, Stukalov A, Vittori S, Muhar M, Lu B, Aichinger M, Jude J, Mueller AC, Gyorffy B, Vakoc CR, Valent P, Bennett KL, Zuber J, Superti-Furga G, Grebien F · Nature Communications 2018
    PMID 29777171DOI
    What this evidence cannot show

    SYSTEM: the AP-MS host is JURKAT, a T-ALL line, whereas KMT2A::AFF1 disease is B-lineage infant leukaemia, so a partner that needs a B-cell or infant proteome cannot appear here and a T-lineage partner can appear spuriously. The bait is a Strep-HA-tagged, SINGLE-COPY, doxycycline-INDUCED transgene, not the endogenous fusion. Prey was recovered from bulk nuclear lysate, so co-purification is not evidence of a direct contact. INCLUSION RULE: the paper kept the top 300 interactions per bait by combined p-value rather than applying a p threshold (Methods, verbatim: "The 300 most significant interactions per bait were retained"). Measured by this beat by reading the cached Supplementary Table 5 xlsx directly on 2026-09-21: 545 of the 2,049 per-bait p-values in the table (26.6%) exceed 0.05, to a maximum of 0.175. This graph's own king analysis ana-the-index-fusion-interactome-is-not-distinctive-and-two-earlier-answers-were-artifacts found the MLL-AF4 column reaches deepest into the weak tail of the seven, so an MLL-AF4 p-value is systematically weaker than the same protein's p-value under another bait and should not be read as a weaker interaction. The index-fusion p-value of 0.129 with 3|2 spectra is not a significant measurement by any conventional criterion, and a second bait is also above 0.05. The pan-fusion label is carried by three baits. Values re-read from the cached xlsx on 2026-09-21.

    Evidence that argues against this (1)
    • IntAct has never curated this dataset (pubid:29777171 returns 0 rows against a working positive control), so no independent curator has re-examined these calls, and the raw data at ProteomeXchange PXD009338 have not been reanalysed here. Nothing in the paper validates this particular prey by an orthogonal assay: of the twelve proteins in this beat, only SETD2 is mentioned anywhere in the paper's body text (counted by regex over the PMC full text, 2026-09-21; SF3A3 appears once, as a named non-selective control). ProteomeXchange/PRIDE 2018
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    KAP-1/TRIM28 is the corepressor for the KRAB zinc-finger protein superfamily and binds SETDB1, a histone H3 lysine-9-specific methyltransferase whose methylation of the H3 tail is sufficient to enhance HP1 binding, providing the route by which KRAB-ZFPs silence euchromatic genes.

    PMID 11959841DOI
    What this evidence cannot show

    Biochemistry and in vitro methylation assays in cultured cells, 2002; not a haematopoietic or fusion system. Read from the abstract.

    Evidence that argues against this (1)
    • TRIM28 also has SETDB1-independent activities, including transcriptional activation, so 'TRIM28 is present' does not imply 'silencing is happening'. Morii M et al. 2024
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In a mouse BCR::ABL1 conditional knock-in model of myeloid leukaemia, deletion of Tif1b (TRIM28) inhibited leukaemia progression, extended survival and sensitised leukaemic cells to dasatinib, with reduced chromatin accessibility at Fosl1-binding motifs; TIF1beta bound the FOSL1 promoter directly in human BCR::ABL1 cells, and TIF1beta expression is elevated in CML blast crisis and AML.

    TIF1beta activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia. · Morii M, Kubota S, Iimori M, Yokomizo-Nakano T, Hamashima A, et al. · Leukemia 2024
    PMID 38734786DOI
    What this evidence cannot show

    A DIFFERENT FUSION (BCR::ABL1), a DIFFERENT LINEAGE (myeloid), and mouse for the genetic arm with a human cell line only for the promoter binding. This project's commonest documented synthesis failure is importing a result from one fusion family into another, so this item is recorded as analogy and must not be read as evidence that KMT2A::AFF1 depends on TRIM28. Read from the abstract.

    Evidence that argues against this (1)
    • Nothing links TRIM28 to a KMT2A fusion in any published experiment; a bounded PubMed search over TRIM28 and KAP1 returns no on-topic record (see data.bounded_literature). Skucha A et al. 2018
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