The infant breakpoint mutilates the reciprocal protein's first PHD finger - so 'the reciprocal product' is at least two different proteins
also called intron 11 breakpoint and AF4-MLL · PHD1 truncation · infant version of AF4-MLL
Where the chromosome breaks decides what the mirror-image protein looks like. In infants the break usually falls in a place that chops the first of four reader modules in half, giving a different protein from the one older patients make.
The same thing, for a scientist
KMT2A breakpoints in t(4;11) cluster in introns 9-11, and intron 11 breaks are the commonest in infant ALL [E1]. Because the reciprocal product begins where the direct product ends, the break position sets the reciprocal protein's N-terminal KMT2A boundary: an intron-11 break starts the reciprocal at exon 12 and disrupts the first PHD finger, which is reported to change the binding of CyP33/PPIE to the PHD domain and therefore the biology of the reciprocal protein [E1]. UniProt places PHD1 at Q03164 residues 1431-1482 and annotates recurrent translocation breakpoint sites at 1362/1363, 1406/1407 and 1444/1445 - the last of which falls inside PHD1 [E2]. The consequence for reading the literature is sharp: the constructs used in the Frankfurt model system are explicitly the infant version [E1], the murine leukaemia experiment that made the reciprocal product famous used an AF4.MLL construct [E3], and no published study has compared an intron-9/10 reciprocal protein with an intron-11 one. A field that treats 'AF4-MLL' as one molecule is pooling at least two.
The arithmetic
Direct product = KMT2A 5' of the break. Reciprocal product = KMT2A 3' of the break. They are complementary, so a break that gives the direct product more KMT2A gives the reciprocal product less, and vice versa. With PHD1 at 1431-1482 and annotated breakpoint sites at 1362/1363, 1406/1407 and 1444/1445 2, breaks in the first two leave PHD1 intact on the reciprocal side; a break at 1444/1445 cuts through it. That is the structural content of the intron-11 observation 1.
Why this is a confound for the prognostic finding and not only a curiosity
Reciprocal transcript expression predicts markedly better survival in t(4;11) infants 4. Breakpoint position is known to vary and is known to change the reciprocal protein. If breakpoint position also predicts outcome, then reciprocal status and breakpoint class are entangled, and no published analysis holds one constant while varying the other. This graph already carries that hypothesis in a different form; the addition here is the mechanism by which the two variables are entangled, namely that the break defines the protein.
| infant typical intron | 11 |
|---|---|
| consequence | PHD1 truncated on the reciprocal side |
| comparison never made | intron-9/10 reciprocal protein versus intron-11 reciprocal protein |
phd1 span
[ 1431, 1482 ]
annotated breakpoint sites
[
[
1362,
1363
],
[
1406,
1407
],
[
1444,
1445
]
]- If the reciprocal product is two proteins, then a therapeutic claim derived from the infant version may not apply to older t(4;11) patients, and the published models are all one version.
- A stratification biomarker built on reciprocal transcript presence would not capture the structural difference that the breakpoint creates, so two patients scored identically could carry different oncoproteins.
- Does an intron-9/10 reciprocal protein with intact PHD1 behave differently from the intron-11 version in any assay? No side-by-side comparison exists.
- Does CyP33/PPIE actually bind the reciprocal product's PHD domain, intact or truncated? The claim is carried forward from wild-type MLL biology.
- Is breakpoint intron recorded alongside reciprocal transcript status in any cohort? The Frankfurt diagnostic archive has the breakpoints and Interfant has the outcomes; whether the same patients appear in both is unknown to this beat.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
KMT2A breakpoints in t(4;11) cluster in introns 9-11 (about 81%) and AF4 breakpoints in introns 3-4 (about 86%); breakpoints within KMT2A intron 11 are most frequently found in infant ALL and appear to change the biology of the reciprocal AF4-MLL fusion protein by disrupting the first PHD finger of the PHD domain, changing CyP33/PPIE binding to that domain; this infant version of the construct was the one used throughout that study.
The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11). · Wilhelm A, Marschalek R · Oncogene 2021What this evidence cannot show
A statement in the introduction of a modelling paper, cited to that group's earlier work on MLL splicing rather than to a dedicated structural or biochemical study of a truncated PHD1 in the reciprocal protein. The functional consequence for CyP33 binding is asserted, not measured here.
Evidence that argues against this (1)
- Whether breakpoint position translates into any clinical difference is unestablished: Interfant-06's multivariable model did not include breakpoint position at all, so there is no cohort analysis in which the two variables have been separated. Agraz-Doblas A et al. 2019
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q03164 places PHD-type zinc finger 1 at residues 1431-1482 and annotates recurrent translocation breakpoint sites at 1362/1363, 1406/1407 and 1444/1445 - the last falling inside PHD1.
UniProt Q03164 (KMT2A_HUMAN), feature table · UniProt Consortium · UniProtKB 2026What this evidence cannot show
Fetched 2026-09-19, primary gene name read back as KMT2A, length 3969. The annotated breakpoint sites are named for KMT2A-AFF4, KMT2A-GAS7, KMT2A-LPP, KMT2A-CENPK and KMT2A-FRYL fusions; UniProt annotates no AFF1 breakpoint site, so these coordinates show the region's span rather than the t(4;11) join specifically.
Evidence that argues against this (1)
- Almost none of this region has been observed experimentally - the breakpoint cluster region is the largest unsolved stretch of KMT2A - so the boundary of PHD1 here is curation, and the functional effect of cutting at 1444 rather than 1406 has not been measured. PDBe 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The murine experiment establishing that the reciprocal product can initiate leukaemia used an AF4.MLL construct expressed in Lin-/Sca1+ progenitors, which induced pro-B ALL, B/T biphenotypic acute leukaemia or mixed-lineage leukaemia, whereas MLL.AF4 alone caused no disease over 13 months.
The AF4.MLL fusion protein is capable of inducing ALL in mice without requirement of MLL.AF4. · Bursen A, Schwabe K, Rüster B, et al. · Blood 2010What this evidence cannot show
One construct, one breakpoint version, murine progenitors; leukaemia arose in only about a third of transplanted mice, and the construct's breakpoint class is not varied. Nothing in this design can speak to whether an intron-9/10 reciprocal protein behaves the same way.
Evidence that argues against this (1)
- In human cord-blood CD34+ cells the same fusion enhanced multilineage engraftment but conferred no serial self-renewal and initiated no leukaemia within 36 weeks, so the murine result does not transfer to the human cell of origin. Prieto C et al. 2017
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Reciprocal AFF1::KMT2A transcript expression was found in 45% (19/43) of t(4;11) cases among 124 Interfant-treated infants and predicted 4-year event-free survival of 62.4% versus 11.7%, with significance retained in a Cox model adjusted for Interfant-06 risk stratification.
Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis. · Agraz-Doblas A, Bueno C, Bashford-Rogers R, et al. · Haematologica 2019What this evidence cannot show
n = 43 t(4;11) patients for the reciprocal comparison; RT-PCR transcript status, not protein; the adjustment covariates are age, white cell count and prednisone response, and breakpoint position is not among them.
Evidence that argues against this (1)
- The reciprocal transcript is only one of the variables that tracks with it: HOXA cluster genes are expressed exclusively in the AF4-MLL-expressing patients in the same cohort, so the survival split may be a HOXA split. Agraz-Doblas A et al. 2019
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Read in full text (PMC10169636): breakpoints upstream of KMT2A exon 11 retain PHD domain I structurally intact for the reciprocal fusion protein, while breakpoints within exon 11 or downstream result in a different folding of PHD domain I, impairing CYP33 binding and the homodimerisation capacity of that domain; and in ALL the infant group shows a clear preference for intron 11 fusions which switches at about 6 months to intron 9.
The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, et al. · Leukemia 2023What this evidence cannot show
Read in full text via Europe PMC fullTextXML (86,330 characters), not abstract only. The PHD-folding consequence is carried into this paper from two cited references rather than measured in it, and the authors state explicitly that whether the breakpoint shift affects clinical outcome is yet unclear. The age-related shift is measured on that centre's 3,401-patient referral series.
Evidence that argues against this (1)
- An absence of testing is not a negative result and the converse also holds: the paper's own statement that the clinical impact is unclear means the structural consequence described here has never been connected to any patient outcome. Agraz-Doblas A et al. 2019
Breakpoint position sets the reciprocal protein's N-terminal KMT2A boundary and whether PHD1 survives.
- related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
The same break defines both products; more KMT2A in one means less in the other.
Supplies the structural mechanism by which breakpoint position and reciprocal status are entangled.
Rests on the complementarity of the two products across the break.