Oncofusion

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Cell statemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q145-irx1-in-hoxa-negative-infants

iALL-HOXA9 — the HOXA-high state of infant KMT2A::AFF1 ALL, and the one everything is modelled on

The other half of these infant leukaemias runs the classic HOXA programme. It has the better outlook, and it is the half that nearly every laboratory model represents.

The same thing, for a scientist

The canonical state of infant t(4;11) ALL: coordinated upregulation of the whole HOXA cluster with HOXA9/HOXA10 high and IRX1 low, a better prognosis than iALL-IRX1, and enrichment for **interferon-gamma response and allograft-rejection (immune) signatures** rather than proliferative ones [E1]. All five pediatric (11-18 y) MLL-AF4 patients in the Andersson cohort fell here [E1]. At chromatin this beat finds it is a **cluster-wide** state: in p179, p247 and TB-05-1939 the whole 107 kb HOXA cluster carries oncoprotein at 2.65-3.23x mean promoter, HOXA9 at 8.6-12.9x, and **IRX1 reads zero in both KMT2A-N antibodies** [E2]. PROM1 (CD133) occupancy is highest in exactly these patients [E2][E1].

Go deeper
The chromatin signature measured here
patientHOXA9 promoter N1/N2HOXA cluster 107 kbIRX1 genePROM1 8 kb
p17912.93 / 8.993.230.027.35
p247 (pediatric)8.95 / 8.452.810.077.72
TB-05-19398.56 / 10.922.650.223.26

Every number is a WITHIN-SAMPLE share: an interval's mean coverage divided by that same library's mean promoter coverage, so 1.0 = an average promoter in that library. GSE252378 has no spike-in and no drug arm, so no between-sample absolute statement is licensed; the only cross-sample quantity used is a ratio of two loci measured inside one library, where the unknown per-library scale cancels. The IRX1 zeros in p179 and p247 are informative (P(zero in both N antibodies by chance) = 0.032 and 0.034); TB-05-1939's is not (P = 0.140) and is reported as weakly measured.

A blind corroboration worth naming

p247 is labelled 'pediatric BALL', not infant, in the GEO characteristics. Symeonidou reports that all five pediatric patients in the Andersson cohort expressed HOXA9 and clustered with iALL-HOXA9 1. That was written into this beat's pre-registration as a prediction before p247's values were read, and p247 came out the second-highest HOXA-occupancy sample in the deposit. One concordant case is not a test, but it was a genuine blind call and is recorded as one.

The state that the field's tools were built for

SEM, the standard t(4;11) line, is here — AFF1 at 5.08x/5.16x on HOXA9/HOXA10 and 0.000x at IRX1 2. The HOXA9/MEIS1 axis is the pharmacodynamic readout for menin inhibitors and the mechanistic core of most published KMT2A::AFF1 work. That this state is well modelled is a strength for it and the reason cell-state-iall-irx1 is the gap.

Facts and figures
locationbone marrow
prognosisbetter than iALL-IRX1
markers
[
  "HOXA9/HOXA10 high",
  "coordinated HOXA cluster expression",
  "IRX1 low or absent",
  "PROM1/CD133 higher than iALL-IRX1"
]
enriched programs
[
  "interferon gamma response",
  "allograft rejection"
]
model systems
[
  "SEM",
  "most published MLL-AF4 mouse models"
]
chromatin q145
{
  "hoxa_cluster_107kb": [
    3.231,
    2.806,
    2.65
  ],
  "hoxa9_promoter": [
    12.93,
    8.99,
    8.95,
    8.45,
    8.56,
    10.92
  ],
  "irx1_gene": [
    0.021,
    0.068,
    0.215
  ]
}
How this could bite us back
  • Because this is the modelled state, a drug can look excellent preclinically and address only the better-prognosis half of patients.
  • HOXA9/MEIS1 collapse as a pharmacodynamic biomarker is only available in this state, which biases trial pharmacodynamics toward the patients who were going to do better anyway.
Still open
  1. Does the coordinated HOXA-cluster occupancy require a single nucleation site, or is the fusion loaded independently at each promoter? The 107 kb window cannot distinguish these and a higher-resolution profile could.
  2. Why is the immune signature the discriminating one on the HOXA side? No mechanism links HOXA9 to interferon-gamma response in this disease.
Every source behind this entry (2)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    iALL-HOXA9 shows coordinated HOXA-cluster upregulation with low IRX1, better prognosis than iALL-IRX1, enrichment for interferon-gamma and allograft-rejection immune signatures, higher PROM1; all pediatric patients in the Andersson cohort fell in this group.

    PMID 33069783DOI
    What this evidence cannot show

    Reanalysis of two existing RNA-seq cohorts; transcriptional only. n = 5 pediatric patients supports the pediatric observation. GSEA hallmark enrichments at these n are hypothesis-generating rather than definitive.

    Evidence that argues against this (1)
    • The immune-signature enrichment could reflect differing non-blast content between samples rather than a blast-intrinsic state; bulk RNA-seq of patient marrow cannot exclude that. Symeonidou V et al. 2021
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In p179, p247 and TB-05-1939 the entire 107 kb HOXA cluster carries oncoprotein at 2.65-3.23x with HOXA9 at 8.6-12.9x, IRX1 reads zero in both KMT2A-N antibodies, and PROM1 occupancy is highest; SEM shows the same reciprocal pattern by AFF1.

    q145 re-analysis of GSE252378: IRX1 and HOXA oncoprotein occupancy across seven KMT2A::AFF1 patients (analyses/q145-irx1-in-hoxa-negative-infants) · Iqbal Lab oncofusion knowledge graph, beat q145 · internal analysis over deposited GSE252378 bigWigs 2026
    What this evidence cannot show

    Three patients plus one cell line, one deposit. TB-05-1939's IRX1 zero is not informative at its depth and is excluded from the absence claim. SEM has AFF1 tracks only, and AFF1 is a poor fusion proxy. Every number is a WITHIN-SAMPLE share: an interval's mean coverage divided by that same library's mean promoter coverage, so 1.0 = an average promoter in that library. **GSE252378 has no spike-in and no drug arm**, so no between-sample absolute statement is licensed; the only cross-sample quantity used is a ratio of two loci measured inside one library, where the unknown per-library scale cancels.

    Evidence that argues against this (1)
    • One deposit, one lab, one assay; seven patients, no RNA-seq. A second cohort profiled by a different group could reverse any of this. Janssens DH et al. 2024
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