Hypothesis: the HOXA-negative, IRX1-negative KMT2A-rearranged blast is a low-oncoprotein-dosage state, not a state whose oncoprotein has been redirected to another programme

[
  "A spike-in-normalised KMT2A-N CUT&RUN in A73051 or a comparable double-negative blast will show a LOWER total genome-wide occupancy than a HOXA-positive KMT2A-rearranged blast processed in the same batch, by at least twofold.",
  "An unbiased genome-wide scan for intervals with N-over-C above 1.75 at p < 1e-5 in A73051 will return no coherent gene programme - operationally, no GO or cell-type signature at FDR 0.05 - whereas the same scan in A93692 (the other KMT2A-AF10 sample, HOXA 20.0x, same institution) will return HOXA and MEIS1-associated terms.",
  "Double-negative blasts will be LESS sensitive to a menin inhibitor ex vivo than HOXA-positive KMT2A-rearranged blasts, because there is less chromatin-bound oncoprotein to displace.",
  "If the fusion transcript is measurable, it will be lower in double-negative blasts, or the breakpoint will remove domains required for chromatin engagement."
]

[
  "exp-q148-spike-in-normalised-paired-n-and-c-cut-and-run-in-a-hoxa-negative-kmt2a-rearranged-blast"
]

[
  "ana-q148-a73051-is-globally-low-oncoprotein-not-hoxa-selectively-low",
  "ana-q148-against-a-coverability-matched-null-the-gmp-like-class-is-enriched-in-one-of-twenty-seven-samples-and-it-is-the-one-that-defined-it"
]

[
  "A genome-wide N-over-C scan in A73051's two KMT2A-N and two KMT2A-C libraries returns a set of intervals with N/C above 1.75 whose annotated genes are coherently enriched for any named cell-type or pathway signature at FDR 0.05, with at least 50 intervals. That would be redirection, not dosage, and it kills this hypothesis. **Compute-only on public bigWigs; not yet run.**",
  "A spike-in-normalised repeat in a double-negative KMT2A-rearranged blast shows total genome-wide oncoprotein occupancy within 1.5-fold of a HOXA-positive blast in the same batch. Dosage then cannot be the explanation.",
  "A double-negative blast responds to a menin inhibitor as well as or better than a HOXA-positive one in a matched ex vivo assay, with at least three samples per arm. The dosage model's therapeutic prediction then fails even if its occupancy prediction holds."
]

[
  {
    "quantity": "n_double_negative_samples_sharing_the_profile",
    "subject": "A73051 and TB920488 - bottom-quartile canonical occupancy, near-parity N/C, GMP class at the matched null",
    "value": 2,
    "units": "samples",
    "n": 2,
    "universe": "GSE252378's two depth-usable HOXA-negative IRX1-negative samples",
    "null": "n = 2 cannot carry a statistic; the smallest attainable exact two-sided p is 1.0",
    "note": "two partners, two lineages, two institutions, one MARGINAL depth"
  }
]