Oncofusion

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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q6-interactome-rna-layer

FTO — highly expressed in MLL-rearranged AML, and the single flattest dependency row in this beat: 0.2% of 1,208 lines

also called ALKBH9 · fat mass and obesity associated · FTO alpha-ketoglutarate dependent dioxygenase

FTO removes the chemical tag from RNA and is unusually abundant in MLL-rearranged myeloid leukaemia. Yet in a screen of over a thousand cancer cell lines, almost none of them need it at all.

The same thing, for a scientist

FTO is an m6A demethylase reported to play an oncogenic role in AML, highly expressed in AMLs with t(11q23)/MLL rearrangements among other genotypes, enhancing leukaemic transformation and inhibiting ATRA-induced differentiation through targets such as ASB2 and RARA [E1]. **Its dependency data are the flattest in this beat**: Chronos mean -0.008 with 0.2% of 1,208 lines depleted below -0.5, and positive index-arm differences of +0.066 B-lymphoid and +0.054 myeloid at the 85.8th percentile of a 466-gene null [E2]. Alias searching is a worked example of inflation rather than recovery: `(MLL OR KMT2A) AND (FTO OR fat mass and obesity)` returns 8 records of which title-checking leaves 2 [E3].

Go deeper
An expression association without a dependency, stated as such

FTO is the cleanest case in the beat of the confounder the whole beat has to survive. It is highly expressed in MLL-rearranged AML 1. It is required by essentially nothing: 0.2% of 1,208 cancer cell lines are depleted for it 2.

Those are compatible - an enzyme can be abundant and dispensable, and the published work uses over-expression and forced-differentiation readouts rather than dependency - but the pairing is exactly what 'an RNA-binding or RNA-modifying protein whose abundance tracks cell state will look important' predicts. A gene that no cell line in a 1,208-line screen needs is not a dependency by any reading of that screen.

This entry therefore records FTO as literature-positive and dependency-negative, and does not reconcile them.

The alias trap, worked

FTO's expansion is the beat's best illustration of alias inflation, the opposite failure to the septin case.

(MLL OR KMT2A) AND FTO returns 3 records. Adding the spelled-out name gives (MLL OR KMT2A) AND (FTO OR fat mass and obesity) = 8. Title-checked, 2 are leukaemia papers and 6 are artefacts: a cognitive-genetics review, a UK Biobank brain-structure study, two massive-localised-lymphoedema case reports in obesity, a palm-oil triacylglycerol study and a grape-juice extract paper 3.

FTO is one of the most heavily studied obesity loci in human genetics, so any query built around it imports that literature. The rule this project wrote after NELFE's RD returned 115 records against a real 2 applies directly: if an alias is short, a common word, or an acronym another field uses, title-check every hit and record the checked number.

Facts and figures
uniprotQ9C0B1
length AA505
gene symbolFTO
uniprot resolutiongene_exact:FTO AND organism_id:9606 AND reviewed:true; one hit; primary gene name read back as FTO; length 505 aa checked
rna functionm6A demethylase (eraser); alpha-ketoglutarate dependent dioxygenase
essentiality
{
  "depmap_common_essential": false,
  "chronos_mean": -0.0082,
  "pct_lines_depleted": 0.2,
  "n_lines": 1208,
  "kmt2a_r_lymphoid_diff": 0.0659,
  "kmt2a_r_myeloid_diff": 0.0539,
  "null_percentile": 85.84
}
pubmed counts
{
  "FTO AND leukemia AND m6A": 77,
  "(MLL OR KMT2A) AND FTO": 3,
  "(MLL OR KMT2A) AND (FTO OR fat mass and obesity)": "8 raw, 2 after title check"
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": 0.1065,
  "chronos_mean_other_leukaemia": 0.0482,
  "difference": 0.0582,
  "pan_essentiality_all_lines": -0.0082,
  "selectivity_rank": 15332,
  "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."
}
How this could bite us back
  • FTO is a major obesity locus with metabolic functions throughout the body; systemic inhibition carries liabilities unrelated to leukaemia.
  • A target required by 0.2% of cancer cell lines has no dependency-based rationale at all, and any programme would be resting entirely on over-expression and differentiation experiments.
  • If FTO and ALKBH5 are redundant erasers, inhibiting one changes bulk m6A very little.
Still open
  1. How can FTO be oncogenic in MLL-rearranged AML and required by 0.2% of 1,208 cancer cell lines?
  2. Do FTO and ALKBH5, the two m6A erasers, buffer each other - both are near-flat in DepMap and a double knockout has not been reported in this disease?
  3. Is FTO's role confined to transformation and differentiation block, phenotypes a proliferation dropout cannot measure?
Every source behind this entry (4)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    FTO plays an oncogenic role in acute myeloid leukaemia as an m6A demethylase: it is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD and/or NPM1 mutations, enhances leukaemic oncogene-mediated cell transformation and leukaemogenesis, and inhibits ATRA-induced differentiation through regulating targets such as ASB2 and RARA by reducing m6A on those transcripts.

    PMID 28017614DOI
    What this evidence cannot show

    Abstract read; full text not read. AML; the MLL association is an expression association across genotypes, not a demonstration of a KMT2A-specific requirement. The transformation experiments use over-expression.

    Evidence that argues against this (1)
    • DepMap gives FTO a Chronos mean of -0.008 with 0.2% of 1,208 lines depleted and POSITIVE differences in both halves of the KMT2A-rearranged index arm. No cell line in a 1,208-line screen meaningfully requires FTO, which is difficult to reconcile with an oncogenic role in established disease however well the over-expression experiments read. Oncofusion knowledge graph (internal analysis) 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.analysis

    DepMap CRISPR (Chronos) gives FTO a mean gene effect of -0.008 across 1,208 lines with 0.2% depleted below -0.5, and index-arm differences of +0.066 (four B-lymphoid) and +0.054 (seven myeloid) against 43 other leukaemia lines, at the 85.8th percentile of a 466-gene null - the flattest row among the m6A machinery genes in this panel.

    What this evidence cannot show

    A flat row cannot distinguish 'not required' from 'redundant with ALKBH5' from 'required only in vivo'. ALKBH5 is the other m6A demethylase and is almost equally flat at 1.4% of lines depleted, so the redundancy reading is available.

    Evidence that argues against this (1)
    • FTO's reported role is in transformation and differentiation block rather than in the survival of established leukaemia cells, and a proliferation dropout measures only the latter. The flat row is evidence about the assay's scope as much as about the gene. Li Z et al. 2017
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Alias-expansion worked example: `(MLL OR KMT2A) AND FTO` returns 3 records; `(MLL OR KMT2A) AND (FTO OR fat mass and obesity)` returns 8, of which title-checking leaves 2 leukaemia papers and 6 artefacts including a cognitive-genetics review, a UK Biobank brain-structure study, two lymphoedema case reports, a palm-oil triacylglycerol study and a grape-juice extract paper.

    PubMed E-utilities esearch counts, alias-expanded and title-checked · NCBI PubMed (queries run 2026-09-20) 2026
    What this evidence cannot show

    Title-checked by reading titles rather than abstracts; an artefact whose title is ambiguous could in principle have been misclassified in either direction.

    Evidence that argues against this (1)
    • One of the three unexpanded hits was itself an artefact - a cognitive-characteristics genetics review in which FTO appears as the obesity locus - so even the narrow query needed title-checking. Neither expansion nor restriction is safe without it. Li Z et al. 2017
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB Q9C0B1 (FTO_HUMAN) is human FTO, 505 amino acids; resolved by gene_exact query with the primary gene name read back as FTO and the length checked.

    What this evidence cannot show

    Single reviewed human hit whose primary gene name equals the query symbol. This project has logged six cases of gene_exact returning a protein that merely lists the queried symbol as a synonym, so the read-back is the point, not the query.

    Evidence that argues against this (1)
    • An accession establishes identity and length. It says nothing about whether this protein matters in KMT2A-rearranged leukaemia, which is what the rest of this entry is for. UniProt Consortium 2026
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