KAT5 / Tip60 - the acetyltransferase in the only direct KMT2A-fusion histone-variant result, and both fusions tested were myeloid

[
  "MLL-AF10",
  "MLL-ENL"
]

[
  "KMT2A::AFF1 (the index fusion)",
  "KMT2A::MLLT3",
  "any lymphoid model"
]

{
  "depmap_common_essential": null,
  "note": "DepMap was not queried for KAT5 in this beat. Before any target claim is made, the KMT2A-rearranged versus other-leukaemia split and the pan-essentiality bar in ana-the-acetyltransferase-signal-is-paralogue-specific-and-does-not-survive-pan-essentiality must both be applied."
}

{
  "subcellular": "Predominantly nuclear and chromatin-associated, but NOT exclusively: in breast and lung cancer cells a cytoplasm-restricted Tip60 retains tumour-suppressor activity, so a nuclear-only description of KAT5 is wrong. UniProt Q92993 (KAT5_HUMAN, Histone acetyltransferase KAT5, 513 aa) was read back only to confirm the identifier; its localisation annotation was not used.",
  "subnuclear": "chromatin at defined loci, and damage-induced foci - but NO named nuclear body. In MLL-AF10 and MLL-ENL leukaemia Tip60 is recruited to the Hoxa9 locus by the fusion, where it acetylates H2A.Z; that is a GENOMIC address in the right disease family, not a spatial compartment. A phase-separation property has been reported for TIP60 and is disrupted by the cancer-associated G400 mutation; that is a condensate claim and is graded against this graph's condensate-evidence standard.",
  "how_shown": "chromatin immunoprecipitation at Hoxa9 plus conditional Tip60 deletion in MLL-AF10 and MLL-ENL leukaemia (PMID 33967269); localisation-restricted constructs with a functional readout (PMID 33155839); in-cell droplet imaging with a point mutant (PMID 39965267)",
  "systems": "murine MLL-AF10 and MLL-ENL myeloid leukaemia for the chromatin work; human breast and lung cancer lines for the cytoplasmic pool",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a"
}

{
  "query": "(Tip60[tiab] OR KAT5[tiab]) AND (KMT2A[tiab] OR MLL[tiab])",
  "records": 7,
  "operand_controls": {
    "(Tip60 OR KAT5 OR HTATIP)[tiab] AND (\"nuclear bodies\" OR nucleolus OR nucleolar OR speckle* OR cytoplasm* OR subnuclear)[tiab]": 57
  },
  "date": "2026-09-21",
  "tool": "PubMed E-utilities esearch",
  "bound": "zero SUBNUCLEAR observations in titles and abstracts; supporting figures not searched"
}

{
  "chronos_mean_kmt2a_rearranged": -0.6615,
  "chronos_mean_other_leukaemia": -0.7024,
  "difference": 0.0409,
  "pan_essentiality_all_lines": -0.6048,
  "selectivity_rank": 13972,
  "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."
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "KAT5 is TIP60. KAT5, KAT7 (HBO1) and KAT8 (MOF) are three different proteins and this graph contains all three; a claim about one must not be transferred to another. KAT5 is Q92993, 513 aa.",
  "expressed_in": {
    "class": 1,
    "summary": "ubiquitous; KAT5/Tip60 is the catalytic subunit of the NuA4/TIP60 complex and is not cell-type restricted."
  },
  "required_in": {
    "class": 2,
    "claim": "In MICE, conditional knockout of Kat5/Tip60 shows a critical requirement for HAEMATOPOIETIC STEM CELL MAINTENANCE at BOTH the embryonic and the adult stage, and the requirement depends on its acetyltransferase activity; Tip60 colocalises with c-Myc in murine HSPCs, Tip60 deletion suppresses Myc target gene expression, and acetylated H2A.Z is enriched at Tip60-bound active chromatin with the acH2A.Z/H2A.Z ratio falling robustly on deletion [E_q69_ct1].",
    "pmids": [
      "32542325"
    ],
    "system_named_in_the_claim": "murine normal haematopoiesis, conditional knockout - not leukaemia, not human, not KMT2A-rearranged",
    "the_developmental_stage_is_part_of_the_answer": "the requirement holds in BOTH embryonic and adult HSCs. That distinguishes KAT5 from its cousin KAT8/MOF, whose HAT activity is required for adult but NOT early fetal haematopoiesis - a difference recorded on gene-kat8 in this graph. Two members of the same acetyltransferase family, opposite answers on the fetal compartment, which is the compartment this disease starts in."
  },
  "not_required_in": {
    "claim": "NO KMT2A-selective requirement. Chronos -0.6615 in the KMT2A-rearranged arm against -0.7024 in other leukaemias, difference +0.0409, rank 13,972 of 17,728 - the ANTI-SELECTIVE half. Pan-essentiality -0.6048, so this is a broadly required gene with no dynamic range problem and no fusion preference.",
    "rescoping_this_forces": "the entry's fusion-recruitment material (Tip60 recruitment in murine MLL-AF10 and MLL-ENL) should be read as 'KAT5 is used by these fusions', which is what the papers show, and NOT as 'KAT5 is a fusion-selective vulnerability', which the screen contradicts. Unselective is not unimportant - -0.60 is a real requirement - but it is not a selectivity."
  },
  "nodes": [
    "cell-type-hsc-bone-marrow",
    "cell-type-fetal-liver-hsc"
  ],
  "context": "murine normal haematopoiesis for the requirement; murine MLL-AF10/MLL-ENL myeloid leukaemia for the fusion-recruitment material already in this entry"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-stem-like-self-renewal"
    ],
    "claim": "In MICE, Tip60 maintains the haematopoietic stem cell state through H2A.Z acetylation at active chromatin and activation of MYC target genes associated with HSC maintenance, cell cycling and DNA repair; the two defining HSC properties the paper names are SELF-RENEWAL and DIFFERENTIATION [E_q69_ct1].",
    "pmids": [
      "32542325"
    ],
    "system_named_in_the_claim": "murine haematopoietic stem and progenitor cells in normal haematopoiesis"
  },
  "bounded_query": {
    "date": "2026-09-21",
    "tool": "NCBI esearch db=pubmed",
    "query": "(KAT5 OR Tip60)[tiab] AND (\"hematopoietic stem\" OR \"haematopoietic stem\")[tiab]",
    "count": 16,
    "on_topic_after_title_check": 1,
    "note": "the single squarely on-topic record is the conditional knockout. A narrower shape, Tip60[tiab] AND (hematopoietic OR haematopoietic)[tiab] AND (maintenance OR self-renewal OR quiescence)[tiab], returns 7 and recovers the same paper.",
    "alias_precision": "Tip60 is a clean token - unlike MOF for KAT8, which returns 28,480 mostly metal-organic-framework records. The KAT5 literature does not have that problem and the counts here are usable as counts.",
    "bound": "titles and abstracts only; supporting figures not searched (brief rule 80)"
  },
  "confidence": "strong",
  "caveats": "Murine conditional knockout in normal haematopoiesis. No human HSC, no KMT2A-rearranged cell, no infant B-lineage measurement. 'HSC maintenance' is a transplant and immunophenotype claim in mouse. The MYC-target mechanism is correlative at the level of the abstract - colocalisation plus expression loss - and the abstract does not report a MYC epistasis experiment. And the DepMap arm places KAT5 in the anti-selective half, so nothing here supports a fusion-selective reading.",
  "counter_evidence": {
    "note": "A TIP60 requirement is not specific to this disease's fusion. ZMYND11-MBTD1, an entirely different leukaemogenic fusion with no KMT2A involvement, induces leukaemia by HIJACKING the NuA4/TIP60 acetyltransferase complex through a PWWP-mediated chromatin association mechanism. So NuA4/TIP60 is a general route into leukaemic transcription that several unrelated fusions take, which is consistent with the anti-selective DepMap placement and argues against a KMT2A-specific TIP60 strategy.",
    "citation": {
      "title": "ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.",
      "year": 2021,
      "venue": "Nat Commun",
      "pmid": "33594072",
      "type": "paper"
    }
  }
}