IKZF1 - the defining co-lesion of every other high-risk B-ALL, and this disease does not use it until after treatment
also called IKZF1 · IKAROS · IK1 · LYF1 · ZNFN1A1 · DNA-binding protein Ikaros · Q13422
IKZF1 makes Ikaros, the protein that tells a young blood cell to become a B cell, and losing it is one of the strongest bad-prognosis markers in childhood leukaemia. Infant KMT2A leukaemia is the exception: it is not damaged at diagnosis. It turns up later, in the leukaemias that come back after chemotherapy.
The same thing, for a scientist
IKZF1 (Q13422, 519 aa) is the single most-cited co-lesion in B-cell precursor ALL: deletions define the poor-risk arm of BCR::ABL1 and Ph-like disease and are embedded in risk algorithms worldwide. Its status in KMT2A-rearranged disease is a **timing statement**, and the graph had no entry to hold it. **At diagnosis in infants: not reported.** The strings IKZF1, and Ikaros, do not appear anywhere in the full text of the index whole-genome study of infant MLL-rearranged ALL - 22 WGS cases, 47 infant MLL-R cases with a 232-gene panel and SNP arrays [E1]. Existing entries in this graph already describe the disease as having 'no recurrent IKZF1'. **At relapse: one of the two commonest alterations.** In 36 relapsed infant and childhood KMT2A-rearranged acute leukaemias, alterations in drug-response genes - **most commonly TP53 and IKZF1** - were present in 64%, rising to **79% of early relapse ALL (9-36 months)** and falling to **9% of very early relapse (< 9 months)**, with a chemotherapy-exposure mutational signature confined to the early-relapse group [E2]. **In adults with the same fusion: present at diagnosis and prognostically heavy.** Among 141 adults with KMT2A-rearranged BCP-ALL, a cohort the authors describe as having a low mutational burden *reminiscent of infant BCP-ALL*, **TP53 and/or IKZF1 alteration** defined a subset with 5-year cumulative incidence of relapse 69.3% vs 36.2% (P = .001) and overall survival 28.1% vs 60.7% (P = .006) [E3]. So IKZF1 in this disease is best read as a **marker of accumulated genomic history**, like TP53 and unlike the RAS-pathway lesions: it is not part of the founding event, it is what the leukaemia acquires when it has had time or treatment. The clinical consequence is that an IKZF1-based risk algorithm imported from other B-ALL subtypes will do nothing at diagnosis in this disease, and may do a great deal at relapse.
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
The bounded absence, and what bounds it
Claim. Neither IKZF1 nor Ikaros occurs in the full text of PMID 25730765, read as 71,491 characters of tag-stripped text from efetch db=pmc on PMC4553269 on 2026-09-20 1.
What that bounds. A whole-genome cohort of 22 infants plus 43 further infant ALL cases on a 232-gene panel with SNP arrays. For a gene whose canonical lesion in B-ALL is a focal intragenic deletion, the SNP-array arm is the relevant assay and it was run on every validation-cohort sample - so this is a stronger negative than the equivalent statement for a point-mutation gene.
What it does not bound. Whether IKZF1 was on the 232-gene panel. Whether a focal intragenic deletion smaller than the array's resolution would have been detected; SNP arrays of that era typically resolve focal deletions well at this locus but not universally. And it is one study.
Subtracted against this graph's own bibliography first, as the rule requires. Existing entries already state 'no recurrent IKZF1' for this disease, so this entry corroborates rather than contradicts what is on disk, and no repository citation was found reporting IKZF1 deletion in de novo infant KMT2A-rearranged ALL.
Why the timing split matters more here than the frequency
Two entries in this graph now rest on the same structural observation, and it deserves stating once plainly:
The lesions this disease carries at diagnosis (RAS-pathway) are subclonal and dispensable. The lesions it carries at relapse (TP53, IKZF1) are selected and persistent, and one of them carries a chemotherapy signature. 2
That is not a description of cooperating lesions. It is a description of a leukaemia whose founding event needs no partner, followed by a treatment that creates one.
The practical readings:
- An IKZF1 result at diagnosis in this disease is uninformative, and importing an IKZF1-based risk score from Ph-like or BCR::ABL1 B-ALL would stratify on a variable that does not vary.
- An IKZF1 result at relapse is informative, and the adult data 3 suggest it is informative in combination with TP53 rather than alone.
- Very early relapse - under 9 months, the worst prognostic group - has neither. 9% versus 79% 2. The mechanism that produces the worst outcomes in this disease has no genomic marker at all, which is a hard limit on what any genomically-guided relapse strategy can reach.
Accession resolution
gene_exact:IKZF1 AND organism_id:9606 AND reviewed:true with gene_primary and length returns one reviewed record:
| accession | primary | synonyms | protein name | length |
|---|---|---|---|---|
| Q13422 | IKZF1 | IK1 IKAROS LYF1 ZNFN1A1 | DNA-binding protein Ikaros (Ikaros family zinc finger protein 1) (Lymphoid transcription factor LyF-1) | 519 |
One row, primary matches. The family is the hazard, not this record. IKZF1 through IKZF5 are all 'Ikaros family zinc finger protein N', and IKZF1's own synonym list contains the bare word IKAROS, so a literature or alias search on 'Ikaros' returns the whole family. The paralogues most likely to be confused are IKZF3 (Aiolos) and IKZF2 (Helios), both lymphoid, both named in leukaemia contexts. Length is a usable discriminator between them, and the accession is asserted here so verify-accessions.py can act on it.
Six C2H2 zinc fingers are annotated in the same record: four N-terminal DNA-binding fingers at 117-139, 145-167, 173-195 and 201-224, and two C-terminal dimerisation fingers at 462-484 and 490-514. The canonical B-ALL dominant-negative isoform IK6 arises by deletion of the DNA-binding fingers while retaining the dimerisation pair, which is why those boundaries are recorded here.
| uniprot | Q13422 |
|---|---|
| gene symbol | IKZF1 |
| length AA | 519 |
| alphafold ID | AF-Q13422-F1 |
| cytoband | 7p12.2 |
| resolution note | gene_exact:IKZF1 AND organism_id:9606 AND reviewed:true with fields=accession,gene_primary,gene_synonym,protein_name,length returned one row: Q13422, primary gene name IKZF1, 519 aa. Fetched from the UniProt REST API on 2026-09-20; zinc-finger coordinates from the same record's feature table the same day. |
| druggability | Not druggable as a loss-of-function lesion. IKZF1 is the substrate whose degradation mediates the action of thalidomide analogues, so the pharmacology that exists for this protein degrades it further rather than restoring it, which is the opposite of what a deleted allele calls for. |
domains — the numbers behind the chart
[
{
"name": "ZnF C2H2-1 (DNA-binding)",
"start": 117,
"end": 139,
"pfam": null
},
{
"name": "ZnF C2H2-2 (DNA-binding)",
"start": 145,
"end": 167,
"pfam": null
},
{
"name": "ZnF C2H2-3 (DNA-binding)",
"start": 173,
"end": 195,
"pfam": null
},
{
"name": "ZnF C2H2-4 (DNA-binding)",
"start": 201,
"end": 224,
"pfam": null
},
{
"name": "ZnF C2H2-5 (dimerisation)",
"start": 462,
"end": 484,
"pfam": null
},
{
"name": "ZnF C2H2-6 (dimerisation)",
"start": 490,
"end": 514,
"pfam": null
}
]cooperating lesion profile
{
"disease": "KMT2A-rearranged acute leukaemia",
"at_diagnosis_infant": "not reported in the index whole-genome study of 47 infant cases; described as not recurrent in existing entries of this graph",
"at_relapse_paediatric": "among the two commonest drug-response gene alterations, 79% of early relapse ALL versus 9% of very early relapse",
"at_diagnosis_adult": "TP53 and/or IKZF1 alteration defines a poor-risk subset of adult KMT2A-rearranged BCP-ALL",
"verdict": "a marker of accumulated genomic history, not a founding partner of the fusion"
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.3691,
"chronos_mean_other_leukaemia": -0.1849,
"difference": -0.1842,
"pan_essentiality_all_lines": 0.0284,
"selectivity_rank": 301,
"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."
}- An IKZF1-based risk score imported from Ph-like or BCR::ABL1 B-ALL would stratify infant KMT2A-rearranged patients on a variable that does not vary at diagnosis, producing a false sense of genomic risk assessment.
- If IKZF1 alterations at relapse are created by chemotherapy exposure, then intensifying chemotherapy to improve early control trades an early failure for a relapse that is harder to treat - and the trial endpoint that would detect this is the genotype of the relapse, which no protocol collects.
- The molecular pharmacology available for IKZF1 - immunomodulatory drugs acting through cereblon - degrades Ikaros. Applying it to a leukaemia whose relapse clone has already lost IKZF1 function is at best redundant and at worst selects further.
- The worst prognostic group in this disease, very early relapse, carries these alterations in 9% of cases. Any relapse strategy built on genomic markers is by construction aimed away from the patients who do worst.
- Was IKZF1 on the 232-gene validation panel of the index study, and did the SNP-array platform resolve focal intragenic IKZF1 deletions? Both are supplementary-table questions and both would convert a silence into a measurement.
- Do IKZF1 alterations at relapse in this disease arise de novo under treatment or expand from a diagnostic subclone? Duplex sequencing has answered this for the RAS lesions and has not been applied to IKZF1.
- Why do adults with the same fusion carry IKZF1 alterations at diagnosis when infants do not, given that both have a low overall mutational burden?
- Does the 9% figure for very early relapse mean those relapses are genomically silent, or that their mechanism is non-genomic - epigenetic, microenvironmental or immune? The worst outcome group in this disease has no marker, and that is the single largest gap this entry found.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Neither IKZF1 nor Ikaros is mentioned anywhere in the full text of the index whole-genome sequencing study of infant MLL-rearranged ALL, which comprised 22 infants by WGS and 47 infant MLL-rearranged cases in total with a 232-gene validation panel and SNP-array copy-number analysis on all validation samples.
The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. · Andersson AK, Ma J, Wang J, et al. · Nature Genetics 2015What this evidence cannot show
A bounded absence from one study, and an absence of reporting rather than a reported zero: the paper does not state that IKZF1 was examined and found intact. Retrieved via efetch db=pmc for PMC4553269 on 2026-09-20, tags stripped before entity unescaping, 71,491 characters; case-insensitive counts for 'IKZF1' and 'Ikaros' were both zero. Graded moderate rather than strong because the negative is inferred from silence, mitigated by the fact that SNP arrays - the right assay for this gene's lesion class - were run on every validation sample.
Evidence that argues against this (1)
- The same locus's canonical B-ALL lesion is a focal intragenic deletion, and whether the SNP-array platform used resolved sub-gene deletions at IKZF1 is not stated; a platform that could not would produce this silence regardless of the truth. Andersson AK et al. 2015
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In 36 infants and children with relapsed KMT2A-rearranged ALL or AML studied by whole-genome and exome sequencing with longitudinal deep sequencing of 257 samples in 30 patients, somatic alterations in drug-response genes - most commonly TP53 and IKZF1 - were present in 64% and were highly enriched in early relapse ALL (79%, 9-36 months) but rare in very early relapse ALL (9%, under 9 months), with a chemotherapy-exposure mutational signature confined to early relapse ALL.
The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia. · Ahlgren L, Pilheden M, Sturesson H, et al. · Nature Communications 2025What this evidence cannot show
A relapse-only cohort of 36 patients split into timing subgroups, so each subgroup is small, and the 64% is for a curated drug-response gene category rather than IKZF1 alone - no IKZF1-specific frequency is quoted here because none is available from the abstract. Mutational-signature attribution on small mutation sets is unstable. Abstract read; full text not retrieved for this entry.
Evidence that argues against this (1)
- The very-early relapse group, which has the worst prognosis, shows these alterations in only 9% of cases and no chemotherapy signature - so the relapse mechanism with the clearest genomic footprint is not the one with the worst outcome, and IKZF1 cannot be the general explanation of relapse in this disease. Ahlgren L et al. 2025
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Among 141 adults with KMT2A-rearranged B-cell precursor ALL identified from 1,091 Philadelphia-negative BCP-ALL patients in three consecutive GRAALL trials, molecular profiling showed a low mutational burden reminiscent of infant BCP-ALL, and TP53 and/or IKZF1 alterations defined a subset with significantly poorer 5-year cumulative incidence of relapse (69.3% vs 36.2%, P = .001) and overall survival (28.1% vs 60.7%, P = .006).
Genetic alterations and MRD refine risk assessment for KMT2A-rearranged B-cell precursor ALL in adults: a GRAALL study. · Kim R, Bergugnat H, Pastoret C, et al. · Blood 2023What this evidence cannot show
Adults, not infants, and IKZF1 is combined with TP53 into a single composite exposure so no IKZF1-specific effect can be extracted. Trial-enrolled patients only. The observation this entry leans on most - that adult KMT2A-r BCP-ALL also has a low mutational burden - is stated without a number in the abstract. Abstract read; full text not retrieved.
Evidence that argues against this (1)
- That adults with the same fusion class carry IKZF1 alterations at diagnosis while infants apparently do not means the difference is developmental or temporal rather than fusion-driven, so the adult risk model should not be imported into infant disease even though the fusion is the same. Andersson AK et al. 2015
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProtKB lists one reviewed human record with primary gene name IKZF1: Q13422, 519 aa, with synonyms IK1, IKAROS, LYF1 and ZNFN1A1, and six annotated C2H2 zinc fingers at 117-139, 145-167, 173-195, 201-224, 462-484 and 490-514.
UniProtKB reviewed human entry Q13422 (IKZF1_HUMAN), retrieved by gene_exact:IKZF1 with fields accession, gene_primary, gene_synonym, protein_name, length and the zinc-finger feature table · UniProt Consortium · UniProt 2026What this evidence cannot show
Fetched 2026-09-20. Coordinates are for the canonical 519-residue sequence; IKZF1 has several annotated isoforms and the leukaemia literature numbers residues from more than one, so a paper's residue number should not be compared to these without checking its isoform. The synonym IKAROS is a bare family word and an alias search on it returns IKZF2-IKZF5 as well.
Evidence that argues against this (1)
- IKZF3 (Aiolos) and IKZF2 (Helios) are lymphoid paralogues frequently named in leukaemia papers, and all family members share the phrase 'Ikaros family zinc finger protein' in their protein names, so reading a protein name back does not separate them - only the primary gene symbol and the accession do. UniProt Consortium 2026
the two commonest drug-response gene alterations at relapse; a composite poor-risk marker in adult KMT2A-r BCP-ALL
- related to →Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word
the relapse half of the timing split this mechanism entry separates out
- co-occurs with →KMT2A-rearranged acute lymphoblastic leukaemia
not reported at diagnosis in infants; 79% of early relapse ALL carries drug-response gene alterations
the full-text string counts behind the IKZF1 bounded absence
named ALL risk gene (control)
IKZF1 deletions are recurrent in SFPQ-ABL1-positive BCP-ALL
SOCS2-correlated genes sit in networks fronted by IKZF1/Ikaros and MEF2C, but Ikzf1 transduction does NOT upregulate Socs2 - the negative control that makes the MEF2C result usable (PMID 25858143)