Oncofusion

start / graph / ana-q199-only-brd4-and-chd4-of-31-fusion-pathway-proteins-carry-the-protein-atlas-cell-cycle-flag-and-the-flag-is-about-mitotic-structures-and-misses-top2a

Analysismoderate confidence 3 of 5: One strong study, or several smaller consistent ones.

Only BRD4 (mitotic chromosome) and CHD4 (mitotic spindle) of 31 fusion-pathway proteins carry the Human Protein Atlas cell-cycle flag (3.5% of all proteins), and the flag, defined by localisation to mitotic structures, does not mark TOP2A, a canonical G2/M gene

A public atlas flags almost none of the proteins in this leukaemia pathway as changing with the cell cycle, but its flag only tracks movement onto mitotic structures. It misses well-known cell-cycle genes such as TOP2A, so it cannot tell us whether the drugs work better in dividing cells.

The same thing, for a scientist

Of 13597 HPA proteins, 479 (3.5%) carry a cell-cycle-dependency annotation. Of the 31 pathway proteins examined, 2 are flagged: BRD4: Mitotic chromosome (biological definition); CHD4: Mitotic spindle (biological definition). Positive control: KIF23, AURKB, ANLN, CENPE are flagged. TOP2A, a canonical G2/M gene, is NOT flagged.

Go deeper
What the flag means

The annotation values are all of the form 'Mitotic chromosome / spindle / midbody (biological definition)': proteins that move onto a mitotic structure. It does not record whether abundance oscillates. TOP2A rises sharply in G2/M and is not flagged, which is the single clearest proof that 'not flagged' cannot be read as 'cell-cycle independent'.

Facts and figures
scriptanalyses/q199-germline-genetics-of-the-fusion-pathway/run.py
ccd total479
hpa total13597
ccd flagged
[
  {
    "gene": "BRD4",
    "in_hpa": true,
    "reliability": "Enhanced",
    "main": "Nucleoplasm",
    "additional": "Mitotic chromosome",
    "ccd": "Mitotic chromosome (biological definition)"
  },
  {
    "gene": "CHD4",
    "in_hpa": true,
    "reliability": "Enhanced",
    "main": "Nucleoplasm",
    "additional": "Cytosol;Mitotic spindle",
    "ccd": "Mitotic spindle (biological definition)"
  }
]
positive control
[
  "KIF23",
  "AURKB",
  "ANLN",
  "CENPE"
]
How this could bite us back
  • If a target's availability depends on cell-cycle phase, a drug could look weak in a quiescent leukaemia reservoir and strong in cycling blasts. This analysis cannot say either way; do not assume phase independence.
Still open
  1. Does menin, DOT1L or fusion chromatin occupancy change across the cell cycle in a KMT2A::AFF1 line? Synchronised or FUCCI-sorted ChIP/CUT&Tag is the experiment; single-cell cell-cycle scoring of the public infant-ALL RNA-seq is the cheap first pass and is suited to the cluster.
Every source behind this entry (2)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    In the Human Protein Atlas subcellular table, 2 of the 31 fusion-pathway proteins examined carry a cell-cycle-dependency annotation - BRD4 (mitotic chromosome) and CHD4 (mitotic spindle) - against 479 of 13,597 proteins (3.5%) overall.

    What this evidence cannot show

    Positive control passed before this was written: KIF23, AURKB, ANLN and CENPE (known mitotic proteins) all carry the flag, so the column is what it appears to be.

    Evidence that argues against this (1)
    • The flag is defined by localisation to mitotic structures, not by abundance cycling: TOP2A, which peaks in G2/M, is not flagged (main location Nucleoplasm, no cell-cycle annotation). So the 29 unflagged pathway proteins may still vary across the cycle. Human Protein Atlas 2025
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    BRD4 is annotated to the mitotic chromosome and CHD4 to the mitotic spindle in the same table, while menin, KMT2A, DOT1L, the AF4/ENL/AF9 family, PSIP1 and CDK9 carry no cell-cycle annotation.

    What this evidence cannot show

    Reliability tiers differ across the set and matter for how far a null is trusted: BRD4 and CHD4 are Enhanced; most unflagged proteins are Supported or Enhanced, but AFF1 and CDK9 are Approved and SIAH1 is Uncertain.

    Evidence that argues against this (1)
    • The Atlas's cell-cycle work uses a small panel of cell lines that the downloaded table does not name, none of which is a KMT2A-rearranged leukaemia line, so whether menin, DOT1L or the fusion changes occupancy across the cycle in these cells is not addressed. Human Protein Atlas 2025
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