TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes

[
  "KMT2A / MLL1 (D2666, D2718)",
  "KMT2B / MLL2",
  "TFIIA"
]

[
  {
    "name": "CS1 (D/GADD)",
    "start": 2666,
    "end": 2667
  },
  {
    "name": "CS2 (D/GVDD)",
    "start": 2718,
    "end": 2719
  }
]

{
  "chronos_mean_kmt2a_rearranged": -0.1249,
  "chronos_mean_other_leukaemia": -0.0881,
  "difference": -0.0368,
  "pan_essentiality_all_lines": -0.1201,
  "selectivity_rank": 4636,
  "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",
  "expressed_in": {
    "class": 1,
    "summary": "broadly expressed threonine endopeptidase; this entry already records that Taspase1 is overexpressed in many cancer cell lines."
  },
  "required_in": {
    "class": 2,
    "claim": "The one haematopoietic cell type with a measured Taspase1 requirement is the THYMOCYTE: in MICE, acute deletion of Taspase1 leads to a MARKED REDUCTION OF THYMOCYTES, and Taspase1-/- animals are smaller with Taspase1-/- mouse embryonic fibroblasts showing impaired proliferation [E_q69_cs1].",
    "pmids": [
      "16951254"
    ],
    "system_named_in_the_claim": "murine acute conditional deletion and germline knockout - normal development, not leukaemia and not human",
    "the_second_cell_type": "craniofacial mesenchyme. TASP1-deficient mice have catastrophic craniofacial malformations associated with inadequate cell proliferation, rescued by compound Cdkn2a deficiency and especially by p16Ink4a deficiency [E_q69_cs2]."
  },
  "not_required_in": {
    "claim": "Weakly selective at best and not a dependency. Chronos -0.1249 in the KMT2A-rearranged arm against -0.0881 in other leukaemias, difference -0.0368, rank 4,636 of 17,728, pan-essentiality -0.1201. The absolute effect is small in both arms.",
    "why_that_matters_for_a_subtraction_layer_gene": "TASP1 is in this graph because it cleaves wild-type KMT2A and does NOT cleave the fusion - it is a subtraction-layer gene, and the interesting question is what the UNcleaved fusion escapes. A near-zero dependency in KMT2A-rearranged lines is what that model predicts: the fusion does not need the protease. The scan is consistent with the subtraction account rather than against it."
  },
  "nodes": [
    "cell-type-early-t-precursor"
  ],
  "context": "murine germline and acute conditional deletion; no human data and no measurement in a KMT2A-rearranged cell"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-cell-cycle-g1-cdk6"
    ],
    "claim": "Taspase1 maintains a PROLIFERATIVE state through cyclin transcription. In MICE, Taspase1 deficiency causes non-cleavage of MLL and MLL2, homeotic transformations, down-regulation of Cyclins E, A and B and UP-REGULATION of p16(Ink4a); MLL and MLL2 directly target E2Fs for cyclin expression, the uncleaved precursor MLL has reduced histone H3 methyltransferase activity in vitro, ChIP shows markedly decreased H3K4 trimethylation at Cyclin E1 and E2 in Taspase1-/- cells, MLL(nc/nc;2nc/nc) MEFs are also impaired in proliferation, and Taspase1-/- cells are resistant to oncogenic transformation [E_q69_cs1].",
    "pmids": [
      "16951254"
    ],
    "system_named_in_the_claim": "murine embryonic fibroblasts and mice - normal cells, not leukaemia and not human"
  },
  "regulates_state": {
    "class": 3,
    "claim": "A SECOND, MLL-INDEPENDENT route to the same state. Taspase1-mediated cleavage of the general transcription factor TFIIA limits transcription of p16Ink4a and p19Arf from the Cdkn2a locus; non-cleaved TFIIA accumulates at both promoters and drives them, and TFIIA - not MLL - is named as the principal Taspase1 substrate for craniofacial morphogenesis [E_q69_cs2].",
    "pmids": [
      "25664857"
    ],
    "why_this_is_load_bearing_for_this_graph": "the standing account of Taspase1 in this project is MLL cleavage. Two papers from the same group say the cell-cycle and morphogenesis phenotypes run substantially through TFIIA and the Cdkn2a locus instead. A KMT2A-centric reading of Taspase1 biology is therefore incomplete, and any proposal to inhibit Taspase1 has an MLL-independent arm nobody has scoped."
  },
  "bounded_query": {
    "date": "2026-09-21",
    "tool": "NCBI esearch db=pubmed",
    "query": "Taspase1[tiab] AND (\"cell cycle\" OR proliferation)[tiab]",
    "count": 10,
    "on_topic_after_title_check": 3,
    "note": "no query in this beat found any Taspase1 measurement in a haematopoietic stem or progenitor cell; the thymocyte result is a single sentence inside the 2006 knockout paper and is the entirety of the blood cell-type evidence for this gene.",
    "bound": "titles and abstracts only; supporting figures not searched (brief rule 80)"
  },
  "confidence": "moderate",
  "caveats": "Murine throughout, normal development rather than leukaemia, no human data. The thymocyte reduction is reported in one sentence of an abstract with no immunophenotype breakdown, so 'early T precursor' is the nearest available node rather than a measured population - the edge is written at weak confidence for that reason. Both papers are from the same laboratory (Hsieh and colleagues), so the MLL-dependent and TFIIA-dependent accounts are one group's programme rather than independent lines.",
  "counter_evidence": {
    "note": "The two accounts of Taspase1's proliferative role compete rather than complement. The 2006 paper attributes the cyclin and p16 phenotype to non-cleavage of MLL and MLL2, showing MLL(nc/nc;2nc/nc) MEFs are also impaired. The 2015 paper, using mice expressing non-cleavable individual substrates, concludes that TFIIA is the PRINCIPAL substrate for the head phenotype and that Cdkn2a - especially p16Ink4a - is where the proliferative effect lands. Both cannot be the whole mechanism; which substrate dominates in a haematopoietic cell has never been tested.",
    "citation": {
      "title": "Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription.",
      "authors": "Takeda S, Sasagawa S, Oyama T, Searleman AC, Westergard TD, Cheng EH, Hsieh JJ",
      "year": 2015,
      "venue": "J Clin Invest",
      "pmid": "25664857",
      "doi": "10.1172/JCI77075",
      "type": "paper"
    }
  }
}