IRX1 is reported as expressed in AML subsets, so its absence from oncoprotein occupancy outside KMT2A::AFF1 is not an absence of IRX1
IRX1 is switched on in some myeloid leukaemias. Our finding is only that the KMT2A fusion protein does not sit on the IRX1 gene outside one fusion type - which is a different claim from IRX1 being off.
The same thing, for a scientist
The bound this entry puts on `ana-q147-irx1-fusion-occupancy-is-confined-to-kmt2a-aff1` is the difference between two measurements that are routinely conflated. **IRX1 expression outside t(4;11), from the published record:** - IRX1 is normally expressed in **pro-B cells** and in **megakaryocyte-erythroid progenitors**, and nowhere else in haematopoiesis, by the TALE-code expression survey [E1]. - IRX1 is **aberrantly active in subsets of AML patients** alongside IRX3 and IRX5, and is overexpressed in megakaryoblastic and myelomonocytic AML cell lines [E2]. - IRX1 is **inactivated in 16.2% of Down-syndrome myeloid leukaemia**, where its loss upregulates the MYC pathway - the opposite polarity to the iALL-IRX1 reading [E3]. **IRX1 occupancy outside KMT2A::AFF1, from this beat:** 0 of 18 samples across five partners, with an upper bound of 16.7% by the rule of three. These are compatible. A gene can be transcribed while the fusion oncoprotein is nowhere near it - and in 11 of GSE252378's 27 samples the disease is AML, exactly where IRX1 expression is reported. **GSE252378 contains no RNA-seq, so no sample in it can be assigned to the published expression subgroup by the published criterion at all.** The conflation this warns against is already an entry here: `concept-an-expression-subgroup-is-not-an-occupancy-subgroup`. **And the three papers do not agree with each other.** Nagel's TALE-code places IRX1 in normal pro-B cells; Kuhn and Symeonidou treat IRX1 as aberrant in t(4;11). That disagreement is unresolved and recorded as `dispute-is-irx1-expressed-in-normal-b-cell-development`; it is **not** resolved by this beat and the three must not be presented as agreeing.
The four possible states, and which this deposit can see
| IRX1 transcript | fusion at IRX1 | interpretation | visible in GSE252378 |
|---|---|---|---|
| high | present | the iALL-IRX1 occupancy state | yes (p279, p318, p454 - occupancy half only) |
| high | absent | IRX1 driven by something other than the fusion | no - needs RNA |
| low | absent | IRX1 simply off | no - indistinguishable from the row above |
| low | present | fusion bound at a silent promoter | yes in principle, not observed |
The deposit cannot separate rows 2 and 3, and that is precisely the ambiguity in the 0-of-18. Nagel's AML expression data make row 2 a live possibility for the 11 AML samples.
| irx1 loss of function in | Down-syndrome myeloid leukaemia, 16.2% of 204 cases |
|---|---|
| gse252378 has rnaseq | false |
| n aml samples in panel | 11 |
| unresolved dispute | dispute-is-irx1-expressed-in-normal-b-cell-development |
irx1 normal expression
[ "pro-B cell", "megakaryocyte-erythroid progenitor" ]
irx1 aberrant expression reported in
[ "AML subsets", "BCP-ALL", "T-ALL", "megakaryoblastic and myelomonocytic AML lines" ]
analyses
[ "ana-q147-irx1-fusion-occupancy-is-confined-to-kmt2a-aff1" ]
- If IRX1 is expressed in some KMT2A-r AML without the fusion on it, then an IRX1-directed agent would be acting on a programme the fusion does not control - and menin inhibition would not touch it. The combination logic differs completely between 'fusion-driven IRX1' and 'fusion-independent IRX1', and nothing currently distinguishes them in patients.
- Is IRX1 transcribed in any of the 18 non-AFF1 GSE252378 samples? A single RNA panel on the same material would convert the 0-of-18 from 'the fusion is not there' into either 'and IRX1 is off' or the much more interesting 'and IRX1 is on without the fusion'.
- Is IRX1 in KMT2A-r AML the same programme as IRX1 in t(4;11) B-ALL? Nagel's regulatory analysis points at GATA1/GATA2 and the megakaryocyte-erythroid axis, which would make them unrelated.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The haematopoietic TALE-code expression survey places IRX1 expression exclusively in pro-B cells within early B-cell development and exclusively in megakaryocyte-erythroid progenitors within myelopoiesis, with IRX2, IRX3 and IRX5 silent in normal B-cell differentiation.
Normal and Aberrant TALE-Class Homeobox Gene Activities in Pro-B-Cells and B-Cell Precursor Acute Lymphoblastic Leukemia · Nagel S, Meyer C · Int J Mol Sci 23:11874 2022What this evidence cannot show
Public-dataset expression profiling plus cell-line models, not primary patient chromatin. Nagel's placement of IRX1 in NORMAL pro-B cells directly conflicts with Kuhn's and Symeonidou's treatment of IRX1 as an aberrant activation in t(4;11); that conflict is unresolved and is recorded separately. This entry cites the disagreement, it does not adjudicate it.
Evidence that argues against this (1)
- Symeonidou & Ottersbach and Kuhn et al. both treat IRX1 as an aberrantly activated gene defining a t(4;11) subgroup, which presupposes it is not simply the normal pro-B-cell programme; if Nagel is right that IRX1 is a normal pro-B-cell factor, the iALL-IRX1 subgroup may be a cell-of-origin signature rather than an oncogenic activation. Symeonidou V et al. 2021
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Analysis of public AML patient expression data reveals aberrant activity of IRX1 in addition to IRX3 and IRX5, and RNA-seq of 100 leukaemia/lymphoma cell lines shows overexpression of IRX1, IRX3 and IRX5 in megakaryoblastic and myelomonocytic AML lines.
The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia · Nagel S, Pommerenke C, Meyer C, MacLeod RAF · Int J Mol Sci 23:3192 2022What this evidence cannot show
Transcript-level, and in AML generally rather than in KMT2A-rearranged AML specifically - the paper does not stratify by fusion partner. So it establishes that IRX1 CAN be on in a myeloid leukaemia, not that it is on in any of the 11 AML samples measured here.
Evidence that argues against this (1)
- If IRX1 in AML is driven by GATA1/GATA2 and the megakaryocyte-erythroid programme, as that paper's own regulatory analysis suggests, then IRX1 expression in AML and IRX1 expression in t(4;11) B-ALL may be two unrelated events sharing a gene name - which would make the comparison this entry draws weaker, not stronger. Nagel S et al. 2022
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Genomic profiling of 204 Down-syndrome myeloid leukaemia cases identifies inactivation of IRX1 in 16.2%, implicated in upregulation of the MYC pathway and proposed as a target for bromodomain inhibition.
Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms · Sato T, Yoshida K, Toki T, et al. · Blood 143:2627-2643 2024What this evidence cannot show
A different paediatric myeloid disease with a different genetic background, and a loss-of-function rather than gain-of-programme event. Cited to establish that IRX1's polarity in paediatric leukaemia is not settled, not to bear on KMT2A-rearranged disease.
Evidence that argues against this (1)
- A loss-of-function role in ML-DS does not preclude a gain-of-programme role in t(4;11); context-dependent opposite roles are common for developmental transcription factors. The two findings constrain any simple model of IRX1 rather than contradicting each other. Sato T et al. 2024
the deposit-level reason occupancy and expression cannot be joined here
closes that entry's first open question in the B-lineage disease rather than in AML
names the AML subgroup Nagel's paper pointed at and measures it in 887 primary patients