Oncofusion

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Geneweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q84-pan-fusion-core

PML / TRIM19 (P29590) - the scaffold of PML nuclear bodies, co-purified with all seven MLL fusions, and never once studied as a KMT2A-fusion partner

also called PML · TRIM19 · MYL · RNF71 · PP8675 · promyelocytic leukemia protein

PML is the protein that builds PML nuclear bodies - small droplet-like hubs inside the nucleus where dozens of other proteins are parked, modified or destroyed. It co-purifies with every MLL fusion tested, which would put the fusion in contact with a named subnuclear compartment, and nobody has ever followed that up.

The same thing, for a scientist

PML (P29590, 882 aa; TRIM19) is the defining and essential component of PML nuclear bodies, a SUMO/SIM-driven membraneless subnuclear compartment. In Skucha 2018 it co-purified with all seven Strep-HA-tagged MLL fusions in Jurkat; MLL-AF4 (= KMT2A::AFF1) gives p = 0.0282 with 4|4 spectra and a clean 0|0 negative control, while MLL-AF9 gives 6.61e-6 with 22|22. Because this project's saturation priorities include subnuclear localization, a pan-fusion interactor that *is* a subnuclear compartment is the most directly on-priority row in this beat. It is also completely unfollowed: `("PML nuclear bodies" OR "PML nuclear body")[tiab] AND (KMT2A[tiab] OR MLL[tiab])` returns **1** record and it is an autophagy review - 0 on topic - against a PML-nuclear-body corpus of 727. The bare `PML[tiab] AND (KMT2A OR MLL)[tiab]` count of 136 is an artefact of the symbol: nearly all of it is cytogenetic panels in which PML-RARA and KMT2A are two rows of the same table, and the token also means progressive multifocal leukoencephalopathy.

Go deeper
The Skucha row

7 of 7 fusions. MLL-AF1p 0.00588 (9|3), MLL-AF4 0.0282 (4|4), MLL-AF9 6.61e-6 (22|22), MLL-CBP 0.00146 (9|9), MLL-EEN 3.39e-4 (17|21), MLL-ENL 1.48e-4 (15|17), MLL-GAS7 0.00944 (13|8); negative control 0|0 1. The MLL-AF4 value is again the weakest of the seven, consistent with that column's known rank-selected depth, and rests on four spectra in each replicate.

What PML is, and why a compartment is different from a partner

PML nuclear bodies are assembled by PML isoforms through SUMO-SIM contacts; mutating the SIM changes body structure isoform-specifically, and C-terminal elements of the individual isoforms control body formation 2. That makes PML not simply another protein in a list - it is the scaffold of a compartment. Two readings of the Skucha row follow and the data cannot separate them: either the fusion (or a sub-pool of it) visits PML bodies, or PML is recovered because both are abundant SUMO-rich nuclear proteins in the same lysate. Co-purification from bulk nuclear lysate cannot distinguish a shared compartment from a contact, and this is the entry where that distinction matters most.

The symbol trap, stated because the count is otherwise misleading

PML is triply ambiguous: the protein/gene, promyelocytic leukaemia the disease and its PML-RARA fusion, and progressive multifocal leukoencephalopathy. PML[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR "MLL-AF4"[tiab] OR "MLL-AF9"[tiab]) returns 136 records; the first 30 by date are, without exception, cytogenetic and fusion-panel papers listing PML-RARA and KMT2A rearrangements as separate diagnostic categories, plus one post-transplant PML (the encephalopathy) case. The interpretable query is the compartment phrase, and it returns 1 with 0 on topic 4. This collision is not in data/symbol-collisions.json as of 2026-09-21 and should be added by whoever owns that file.

Localization, which is the point of this entry

UniProt P29590 records Nucleus, PML body with four independent ECO:0000269 experimental citations and a cytoplasmic pool with one; Nucleus, nucleoplasm and Nucleus, nucleolus are present but uncoded, and the nucleolar line is the interesting one for this graph given the standing nucleolar convergence. Per the standing rule, the uncoded lines are recorded as uncoded rather than discarded. There is no measurement of PML body number, size or composition in any KMT2A-rearranged cell.

Facts and figures
uniprotP29590
length AA882
accession resolutionResolved live 2026-09-21: gene_exact:PML AND organism_id:9606 AND reviewed:true returns exactly one row, gene_primary PML, P29590, PML_HUMAN, 882 aa, synonyms MYL PP8675 RNF71 TRIM19. Matches Skucha's table. Note that 882 aa is the canonical isoform; PML expresses many C-terminally variant isoforms (PML-I to PML-VII) whose behaviour in body formation differs, so a single length is a weaker identifier here than usual.
localizationNucleus (with a smaller cytoplasmic pool)
subnuclear localizationPML nuclear bodies (ND10) - PML is the scaffold, not merely a resident. UniProt also lists nucleoplasm and NUCLEOLUS, both uncoded.
localization evidenceUniProt P29590, fetched 2026-09-21: 'Nucleus, PML body' carries FOUR ECO:0000269 experimental citations; 'Cytoplasm' one; 'Nucleus', 'Nucleus, nucleoplasm' and 'Nucleus, nucleolus' are UNCODED, as are the endoplasmic-reticulum and early-endosome membrane lines (the last two ECO:0000250, by similarity). The uncoded nucleolar line is recorded here rather than discarded because this graph has a standing nucleolar question.
shown for fusionKMT2A::AFF1 (MLL-AF4) plus all six other Skucha baits, by co-purification only. NO independent experiment ties PML or PML nuclear bodies to a KMT2A fusion in any system. Separately, PML is one half of PML-RARA, a different fusion family already in this graph - that is a coincidence of the gene, not evidence about KMT2A.
symbol collisionPML is triply ambiguous - the gene/protein, promyelocytic leukaemia (and the PML-RARA fusion), and progressive multifocal leukoencephalopathy. The first 30 records of the bare-symbol query, read by title on 2026-09-21, are cytogenetic and fusion-panel papers listing PML-RARA and KMT2A rearrangements as separate diagnostic categories, plus one post-allogeneic-transplant case of the encephalopathy (PMID 32484854 in a sibling query). NOT PRESENT in data/symbol-collisions.json as of 2026-09-21; reported to the coordinator rather than added, because this beat does not own that file.
graph contextThis graph already holds fusion-pml-rara, protein-pml-domains, localization-pml-nuclear-bodies-pmlrara and concept-why-pml-rara-became-curable - all about PML as the 5' partner of a different fusion. None of them concerns PML as an interactor of a KMT2A fusion, and there was no gene-pml entry before this one.
skucha 2018
{
  "bait": "MLL-AF4 (= KMT2A::AFF1)",
  "p_value": 0.0282,
  "spectral_counts": "4|4",
  "n_fusions_of_seven": 7,
  "negative_control_counts": "0|0",
  "per_bait": {
    "MLL-AF1p": "0.00588 (9|3)",
    "MLL-AF4": "0.0282 (4|4)",
    "MLL-AF9": "6.61e-06 (22|22)",
    "MLL-CBP": "0.00146 (9|9)",
    "MLL-EEN": "0.000339 (17|21)",
    "MLL-ENL": "0.000148 (15|17)",
    "MLL-GAS7": "0.00944 (13|8)"
  },
  "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",
  "cultured human cells - PML isoform reconstitution and body formation",
  "no KMT2A-rearranged cell of any kind, and no measurement of PML body number or composition in one"
]
bounded literature
{
  "query": "(\"PML nuclear bodies\"[tiab] OR \"PML nuclear body\"[tiab]) AND (KMT2A[tiab] OR MLL[tiab])",
  "querytranslation": "(\"PML nuclear bodies\"[Title/Abstract] OR \"PML nuclear body\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract])",
  "count": 1,
  "on_topic_after_title_check": 0,
  "date": "2026-09-21",
  "tool": "NCBI esearch db=pubmed",
  "operand_controls": "compartment phrase alone 727; MEN1 through the identical shape 85",
  "bare_symbol_query": "PML[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab]) returns 136 - uninterpretable, see symbol_collision",
  "names_tried": [
    "PML",
    "TRIM19",
    "PML nuclear body",
    "PML nuclear bodies"
  ],
  "bound": "Titles and abstracts only; supporting figures not searched."
}
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": "PML",
  "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
  • PML is a tumour suppressor with an established role in maintaining normal haematopoietic stem cells; anything that disrupts PML bodies in an infant is acting on the compartment the normal graft needs.
  • Arsenic trioxide degrades PML and is already a clinical agent, so a PML-directed idea here would inherit a drug whose entire clinical rationale is a different fusion - which is exactly the partner-imported reasoning this project keeps having to undo.
  • If the co-purification reflects shared condensate residence rather than a contact, then every intervention designed from this row targets a compartment, not an interface, and will have proteome-wide consequences.
Still open
  1. Does KMT2A::AFF1 localise to, or adjacent to, PML nuclear bodies in a t(4;11) B-ALL line? A two-colour immunofluorescence experiment would settle a question no paper has asked.
  2. Is the co-purification SUMO-dependent? If the fusion is recovered with PML because both are SUMO-rich, a SUMOylation-deficient bait or a SIM mutant should abolish it.
  3. Are other PML-body clients (DAXX, SP100, SUMO1/2, RNF4) present in the Skucha 960-protein network? A body-level signature would be far stronger than one scaffold protein.
  4. Do PML bodies change in number or size when the fusion is degraded or when menin is inhibited?
Every source behind this entry (4)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    PML co-purified with all seven Strep-HA-tagged MLL fusions in isogenic Jurkat cells, with MLL-AF4 (= KMT2A::AFF1) at combined p = 0.0282, 4|4 spectral counts, negative control 0|0.

    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. PML is the scaffold of a SUMO-driven membraneless compartment, so co-purification from bulk nuclear lysate is especially hard to interpret: shared residence in a condensate, co-precipitation of a condensate, and a protein-protein contact all give the same result. Four spectra per replicate. 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. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    PML nuclear bodies are assembled by PML isoforms through SUMO-SIM interactions, and SIM mutation plus specific C-terminal elements of individual PML isoforms critically determine whether and how the bodies form.

    PMID 28851805DOI
    What this evidence cannot show

    High-resolution microscopy of PML isoforms in cultured human cells, largely in reconstitution; not a haematopoietic system and not a fusion system. Read from the abstract. Cited for what PML bodies are, not for anything about leukaemia.

    Evidence that argues against this (1)
    • Isoform-reconstitution experiments can overstate a scaffold's sufficiency; the endogenous body contains dozens of client proteins whose contributions are not tested here. Nakahara F et al. 2014
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

    PML has an established role in haematopoietic and leukaemic stem cell maintenance, which is the compartment infant KMT2A::AFF1 disease is thought to arise in.

    The role of PML in hematopoietic and leukemic stem cell maintenance. · Nakahara F, Weiss CN, Ito K · Int J Hematol 2014
    PMID 24488785DOI
    What this evidence cannot show

    A REVIEW, cited as a map rather than as primary evidence, and 2014 - the primary experiments behind it are mouse chronic myeloid leukaemia and normal HSC work, not KMT2A-rearranged disease and not B-lineage. Read from the record metadata and abstract only. This item is deliberately confidence 'moderate' and should be replaced by the underlying primary papers by whoever next touches this entry.

    Evidence that argues against this (1)
    • A role in leukaemic stem cell maintenance established in CML says nothing about an infant B-lineage KMT2A::AFF1 blast, and this graph has repeatedly been burned by importing a partner's biology across fusion families. Skucha A et al. 2018
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    No paper in PubMed titles or abstracts connects PML nuclear bodies to KMT2A or MLL: the compartment-phrase query returns one record, an autophagy review, against a PML-nuclear-body corpus of 727.

    What this evidence cannot show

    Query: ("PML nuclear bodies"[tiab] OR "PML nuclear body"[tiab]) AND (KMT2A[tiab] OR MLL[tiab]); querytranslation returned by the API: ("PML nuclear bodies"[Title/Abstract] OR "PML nuclear body"[Title/Abstract]) AND ("KMT2A"[Title/Abstract] OR "MLL"[Title/Abstract]); count 1, the single hit being PMID 32917124, a review of autophagy in AML - 0 on topic. Operand controls: the compartment phrase alone returns 727; the identical query shape with MEN1 substituted returns 85, so the instrument can return a one. Singular and plural were both run. BOUND: titles and abstracts only - a PML-body image in a supporting figure of a KMT2A paper is unreachable by this query, which is the failure mode this project has already documented.

    Evidence that argues against this (1)
    • An abstract-level zero cannot see a supporting figure, and immunofluorescence panels are exactly the kind of result that lives in one. NCBI E-utilities 2026
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