FANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all

{
  "depmap_common_essential": false,
  "chronos_mean": -0.2603,
  "frac_lines_below_minus_0_5": 0.113
}

{
  "chronos_mean_kmt2a_rearranged": -0.7601,
  "chronos_mean_other_leukaemia": -0.3626,
  "difference": -0.3975,
  "pan_essentiality_all_lines": -0.2603,
  "selectivity_rank": 35,
  "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."
}

{
  "kmt2a_records_raw": 0,
  "kmt2a_records_title_checked": 0,
  "leukaemia_records": 12,
  "aliases_searched": [
    "FANCL",
    "PHF9",
    "POG",
    "FAAP43"
  ],
  "kmt2a_query": "(FANCL[tiab] OR PHF9[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"mixed-lineage leukemia\"[tiab])",
  "leukaemia_query": "(FANCL[tiab] OR PHF9[tiab]) AND (leukemia[tiab] OR leukaemia[tiab])"
}

{
  "subcellular": "Nucleus AND mitochondrion, from one gene with no isoform explanation. The Fanconi anaemia core complex - which contains FANCL - is chromatin-associated: fluorescent-tagged core components colocalise in cytoplasm and nucleus, chiefly in chromatin, exist as foci on chromatin at the G1-S border, progressively diffuse and migrate to the NUCLEAR PERIPHERY, and are completely excluded from condensed chromosomes by mitosis; mitomycin C increases complex binding to chromatin. Separately and unambiguously, FANCL protein is present in MITOCHONDRIA in both untreated and oligomycin/antimycin-treated cells, and its ubiquitin ligase activity is NOT required for that mitochondrial localisation - FANCL supports Parkin-mediated mitophagy there. UniProt Q9NW38 was used only to confirm the accession (FANCL_HUMAN, 375 aa, gene synonym PHF9).",
  "subnuclear": "chromatin foci with a cell-cycle itinerary, not a named body: foci on chromatin at the G1-S border, progressive diffusion toward the NUCLEAR PERIPHERY through S phase, and complete exclusion from condensed chromosomes by mitosis. No nucleolar, speckle, PML-body or paraspeckle assignment for FANCL exists in any source read for this beat.",
  "how_shown": "fluorescent-tagged FA core components with chromatin-fibre analysis and mitomycin C treatment across the cell cycle (PMID 15256425); mitochondrial fractionation and imaging with a ligase-dead mutant and CRISPR knockouts (PMID 35644338)",
  "systems": "human cell lines; no leukaemia and no KMT2A-rearranged system",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a"
}

{
  "query": "FANCL[tiab] AND (localiz*[tiab] OR nuclear[tiab] OR cytoplasm*[tiab] OR foci[tiab] OR chromatin[tiab])",
  "records": 45,
  "records_in_leukaemia": 0,
  "names_searched": [
    "FANCL",
    "PHF9",
    "FAAP43",
    "Fanconi anemia core complex"
  ],
  "date": "2026-09-21",
  "tool": "PubMed E-utilities esearch",
  "bound": "zero in titles and abstracts; supporting figures not searched"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "expressed_in": {
    "class": 1,
    "summary": "broadly expressed; FANCL is the E3 ligase subunit of the Fanconi anaemia core complex and is not cell-type restricted."
  },
  "required_in": {
    "class": 2,
    "claim": "In NORMAL HUMAN CD34+ STEM AND PROGENITOR CELLS, suppression of FANCL expression results in fewer beta-catenin-active cells and INHIBITS EXPANSION OF MULTILINEAGE PROGENITORS; FANCL-deficient cells show diminished capacity to activate beta-catenin and reduced transcription of the Wnt-responsive targets c-Myc and Cyclin D1 [E_q69_ct1].",
    "pmids": [
      "22653977"
    ],
    "system_named_in_the_claim": "primary HUMAN CD34+ haematopoietic stem and progenitor cells, shRNA knock-down - human and primary, but normal marrow rather than leukaemia"
  },
  "required_in_leukaemia": {
    "class": 2,
    "claim": "FANCL is one of the more KMT2A-SELECTIVE genes in the whole scan: Chronos -0.7601 in the 11 KMT2A-rearranged lines against -0.3626 in the 43 other leukaemia lines, difference -0.3975, rank 35 of 17,728, pan-essentiality -0.2603 so there is ample dynamic range and no floor compression.",
    "reading": "a difference is not a dependency - the scan cannot say the fusion causes the requirement. But of the thirteen genes in this tranche carrying a scan value, FANCL sits third-most selective after MEF2C (rank 8) and ahead of HDGFL2 (415), and unlike TOP2A the measurement is interpretable."
  },
  "nodes": [
    "cell-type-hsc-bone-marrow"
  ],
  "context": "human CD34+ HSPC for the requirement; murine FA-pathway-deficient mice for the state; DepMap cancer lines for the selectivity"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-quiescence"
    ],
    "claim": "The FA pathway is what makes EXIT FROM QUIESCENCE survivable. In MICE, DNA damage in haematopoietic stem cells is a direct consequence of inducing HSCs to LEAVE their homeostatic quiescent state under conditions modelling physiological stress such as infection or chronic blood loss; repeated activation out of dormancy causes attrition of normal HSCs, and in mice with a NON-FUNCTIONAL FANCONI ANAEMIA DNA REPAIR PATHWAY it causes complete collapse of the haematopoietic system, phenocopying the bone marrow failure of Fanconi anaemia patients [E_q69_cs1].",
    "pmids": [
      "25707806"
    ],
    "system_named_in_the_claim": "murine haematopoietic stem cells, normal and FA-pathway-deficient - not leukaemia and not human"
  },
  "why_this_is_the_sharpest_state_answer_in_the_tranche": "the requirement is CONDITIONAL ON THE STATE TRANSITION, not on either state. A dormant FA-deficient HSC is fine and a cycling one is fine; what kills is the transition, repeated. That is a cell-state dependency of a kind no steady-state measurement and no proliferation screen can detect, and it is the clearest illustration in this tranche of why cell state is a different axis from cell type.",
  "the_leukaemia_relevance_that_is_NOT_established": "an infant leukaemic blast is a cell being driven repeatedly out of quiescence. If the FA pathway is what licenses that transition, a KMT2A-selective FANCL dependency (rank 35 of 17,728) would have a mechanism. NOTHING in the cited literature tests this: the dormancy work is normal murine HSCs and the selectivity is a cancer-line screen. It is written here as a lead and as the entry's open question, not as a finding.",
  "bounded_query": {
    "date": "2026-09-21",
    "tool": "NCBI esearch db=pubmed",
    "query": "(FANCL OR \"Fanconi anemia\" OR \"Fanconi anaemia\")[tiab] AND (dormancy OR dormant OR quiescent OR quiescence)[tiab] AND (\"hematopoietic stem\" OR \"haematopoietic stem\")[tiab]",
    "count": 24,
    "on_topic_after_title_check": 1,
    "caveat_on_the_operand": "the query is dominated by the PATHWAY term, not the gene. FANCL[tiab] AND (hematopoie* OR haematopoie* OR \"stem cell\" OR germ cell OR primordial)[tiab] returns 28. The dormancy paper reaches this entry through 'Fanconi anaemia pathway' and would be invisible to a FANCL-only search - brief rule 71 in its exact form, a pathway named by something other than its member gene.",
    "bound": "titles and abstracts only; supporting figures not searched (brief rule 80)"
  },
  "confidence": "moderate",
  "caveats": "The dormancy result is about the FA PATHWAY, not about FANCL. FANCL is one subunit of a multi-protein core complex and the mouse models used in that work are not Fancl-null; attributing the dormancy phenotype to FANCL specifically would be a subunit-for-complex substitution of exactly the kind brief rule 64 warns about. The beta-catenin result IS FANCL-specific and IS human and primary, but it is a knock-down with a non-canonical, non-proteolytic K11 ubiquitin chain mechanism reported by one group and not independently replicated in the records retrieved.",
  "counter_evidence": {
    "note": "The two results do not sit comfortably together. The dormancy paper attributes FA-pathway loss to a DNA-REPAIR failure at the moment of cycle entry; the beta-catenin paper proposes that FANCL's haematopoietic role is a WNT SIGNALLING one, explicitly asking whether 'loss of E3 ubiquitin ligase activity accounts for the hematopoietic stem cell defects' and answering with a non-repair mechanism. Both cannot be the whole story, and this entry does not choose between them.",
    "citation": {
      "title": "Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells.",
      "authors": "Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, Moehrle B, Brocks D, Bayindir I, Kaschutnig P, Muedder K, Klein C, Jauch A, Schroeder T, Geiger H, Dick TP, Holland-Letz T, Schmezer P, Lane SW, Rieger MA, Essers MA, Williams DA, Trumpp A, Milsom MD",
      "year": 2015,
      "venue": "Nature",
      "pmid": "25707806",
      "doi": "10.1038/nature14131",
      "type": "paper"
    }
  }
}