At the DNA level almost every KMT2A-rearranged patient has a reciprocal allele - 94% across partners, and 5% have nothing else
also called reciprocal allele frequency · 94% reciprocal · reciprocal-only patients · DCAL reciprocal counts
Nearly every child with this kind of leukaemia carries both halves of the chromosome swap in their DNA - not just the famous half. In about one in twenty, the famous half is missing altogether and only the mirror-image gene is there.
The same thing, for a scientist
The Frankfurt Diagnostic Center of Acute Leukemia, reporting on its own recombinome, states that balanced translocations make up about 70% of KMT2A rearrangements, that of 102 fusion genes only 10 were per se out-of-frame, and that an additional reciprocal fusion gene is generated in 94% of cases; 114 of 2,454 patients (about 5%) were diagnosed with only the reciprocal fusion allele and no KMT2A-X allele at all [E1]. For t(4;11) specifically, about 80% of patients exhibit both reciprocal fusion alleles and 20% appear to encode only KMT2A::AFF1; genomic analysis of that 20% found cryptic and three-way translocations, in-frame reciprocal KMT2A fusions to novel partners such as NFKB1 and RABGAP1L, out-of-frame reciprocal fusions to PBX1, ELF2, DSCAML1 and FXYD6, and patients carrying solitary 3'-KMT2A segments - leading those authors to propose that all t(4;11) patients carry a reciprocal KMT2A allele of some kind [E2]. The number this graph should quote depends on the question: 94% for 'is there a reciprocal allele', about 45% for 'is there a reciprocal transcript'.
Three different numbers that are all correct
94% - a reciprocal fusion gene is generated in 94% of KMT2A rearrangements across partners 1.
~80% - t(4;11) patients with both reciprocal fusion alleles detectable, against 20% with only the direct fusion; and on genomic re-analysis the 20% turn out to carry a reciprocal KMT2A allele fused to something else, or a solitary 3'-KMT2A fragment 2.
45% - t(4;11) patients whose reciprocal transcript is actually expressed, by RT-PCR, in the Interfant cohort 3.
These are not in conflict; they measure allele generation, allele survival and transcription. The gap between 80-94% and 45% is the part with clinical consequences, and it is the part nobody has explained.
The five percent that inverts the whole framing
114 of 2,454 patients - about 5% - were diagnosed with the reciprocal fusion allele only, with no KMT2A-X allele 1. In those patients the 'reciprocal' product is the only KMT2A fusion present. Whatever the disease is being driven by, it is not a menin-binding, direct 5' KMT2A fusion, because there is not one. That population is larger than several partner classes this graph gives dedicated entries to, and no menin-inhibitor eligibility criterion excludes it or selects for it.
What is NOT known: whether the fraction changes between diagnosis and relapse
The Frankfurt group's stated motivation is to explain the elimination of the AF4-MLL allele in about 40% of patients, a loss they attribute to a clonal evolutionary process 4. That framing implies a diagnosis-to-relapse change. No paired measurement exists. Searched 2026-09-19: (AF4-MLL OR AF4.MLL) AND (relapse OR paired OR longitudinal) returns 4 records, none of which reports reciprocal status at two timepoints in the same patients; AF4-MLL AND minimal residual disease returns 2, both methodological; der(4) allele loss leukemia returns 0. The genomic-breakpoint MRD assays that exist are keyed to the direct fusion junction 5. So the 40% figure is a cross-sectional observation being read as a longitudinal one.
| metric | fraction of patients with a reciprocal KMT2A fusion allele |
|---|---|
| value PCT any partner | 94 |
| value PCT t411 both alleles | 80 |
| value PCT t411 transcript expressed | 45 |
| balanced translocation fraction PCT | 70 |
| population | KMT2A-rearranged acute leukaemia referred to the Frankfurt DCAL (E1, E2) and infant B-ALL on Interfant 99/06 (E3) |
| region | Germany / European referral |
| year | 2020 |
| source | PMID 32294539, 17410185, 30679323 |
| bounded absence | No study reports reciprocal fusion status at both diagnosis and relapse in the same patients. Queries run 2026-09-19: '(AF4-MLL OR AF4.MLL) AND (relapse OR paired OR longitudinal)' = 4 records, none longitudinal; 'AF4-MLL AND minimal residual disease' = 2, both methodological; 'der(4) allele loss leukemia' = 0. Note that 'der(4)' in a compound query silently breaks the PubMed parser, so it was run as a bare phrase. |
reciprocal only patients — the numbers behind the chart
{
"n": 114,
"denominator": 2454,
"pct": 4.6
}- In about 5% of KMT2A-rearranged patients the only KMT2A fusion present is the reciprocal one, which has no menin-binding motif. A menin inhibitor prescribed on a KMT2A-rearranged label would be engaging a protein those patients do not have.
- MRD assays keyed to the direct junction cannot detect selection for or against the reciprocal allele under treatment, so a resistance mechanism of exactly this shape would be invisible to routine monitoring.
- Both frequency estimates come from one diagnostic centre and one trial consortium that shares its typing; there is no independent count.
- What is reciprocal status at relapse in patients who were reciprocal-positive at diagnosis? No paired measurement has been published and the assay is one RT-PCR.
- Of the 114 reciprocal-only patients, what partner genes are involved, what diseases did they present with, and how did they do? They are counted in one sentence and characterised nowhere.
- Why does allele presence (80-94%) exceed transcript expression (45%) by so much in t(4;11)? Silencing, out-of-frame joins, an unexpected partner the RT-PCR cannot see, and clonal loss are four different explanations with four different clinical meanings.
- Do the DCAL series and the Interfant cohort share patients? If they do, the numbers are not independent; if they do not, no independent cohort has counted reciprocal alleles at all.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Across the Frankfurt DCAL recombinome, balanced translocations comprise about 70% of KMT2A rearrangements, 10 of 102 fusion genes were per se out-of-frame, an additional reciprocal fusion gene is produced in 94% of cases, and 114 of 2,454 patients (about 5%) were diagnosed only with the reciprocal fusion allele and no KMT2A-X allele.
The reciprocal world of MLL fusions: A personal view. · Marschalek R · Biochim Biophys Acta Gene Regul Mech 2020What this evidence cannot show
A single diagnostic centre's referral series, explicitly framed by its author as a personal view; referral bias toward complex or difficult-to-type cases is plausible and unquantified, and the 94% is a count of alleles detectable by that centre's assays rather than of alleles transcribed or translated. This is also the laboratory whose position is that reciprocal fusions matter, so the enumeration and the interpretation are not independent.
Evidence that argues against this (1)
- Whether these reciprocal alleles are functional is a separate question that the same series cannot answer: at the transcript level the reciprocal product is expressed in only about 45% of t(4;11) cases. Agraz-Doblas A et al. 2019
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
About 80% of t(4;11) patients exhibit both reciprocal fusion alleles and 20% appear to encode only MLL.AF4; genomic analysis of the latter group found cryptic and three-way translocations, in-frame reciprocal MLL fusions to novel partners including NFKB1 and RABGAP1L that were actively transcribed, out-of-frame reciprocal fusions to PBX1, ELF2, DSCAML1 and FXYD6 causing haploinsufficiency of genes normally expressed in haematopoietic cells, and patients carrying only solitary 3'-MLL gene segments - leading the authors to propose that all t(4;11) patients carry a reciprocal MLL allele.
Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4.MLL fusion allele. · Kowarz E, Burmeister T, Lo Nigro L, et al. · Leukemia 2007What this evidence cannot show
2007, genomic DNA analysis of a selected subgroup (the reciprocal-negative 20%) rather than a consecutive cohort; n is not stated in the abstract; the proposal that all t(4;11) patients carry a reciprocal allele is an inference from a sampled subgroup.
Evidence that argues against this (1)
- Transcript-level measurement in a uniformly treated cohort finds the reciprocal expressed in fewer than half of t(4;11) cases, so the presence of an allele and the presence of a product diverge sharply. Agraz-Doblas A et al. 2019
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The reciprocal AF4-MLL transcript was expressed in 45% (19 of 43) of t(4;11)-positive patients among 124 de novo infant B-ALL cases diagnosed and treated uniformly on Interfant 99/06 protocols.
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 for the reciprocal denominator; RT-PCR on diagnostic material only; transcript detection depends on primer placement, which cannot see a reciprocal allele fused to an unexpected partner - exactly the situation the genomic study describes.
Evidence that argues against this (1)
- Genomic analysis of t(4;11) patients scored reciprocal-negative found reciprocal KMT2A alleles fused to other partners and actively transcribed, so an RT-PCR designed around the AFF1 junction will under-count reciprocal expression by an unknown amount. Kowarz E et al. 2007
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The elimination of the AF4-MLL allele occurs in about 40% of patients and appears to worsen disease outcome, and is interpreted as a clonal evolutionary process selecting for a more aggressive leukaemia.
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
Stated in the introduction and discussion of a modelling paper as the motivation for its experiments, citing the Interfant cross-sectional analysis; the paper itself contributes no patient data and the word elimination imports a longitudinal process that the cited cross-sectional data cannot demonstrate.
Evidence that argues against this (1)
- The cross-sectional source reports expression status at diagnosis, not loss over time, and its own framing is a prognostic marker rather than a clonal-evolution claim. Agraz-Doblas A et al. 2019
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Genomic breakpoint sequences from KMT2A-rearranged patients are used to monitor minimal residual disease, and the recombinome study frames this as its direct clinical translation.
The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, et al. · Leukemia 2023What this evidence cannot show
MRD assays are built on the patient-specific genomic junction; the abstract does not state whether the reciprocal junction is ever used, and this beat found no report of reciprocal-junction MRD monitoring.
Evidence that argues against this (1)
- Because MRD assays are keyed to one junction, a clone that lost the reciprocal allele and a clone that retained it are indistinguishable by that assay, so the material that would answer the diagnosis-to-relapse question is not routinely generated. Marschalek R 2020
Quantifies how often the reciprocal allele exists and how often it is transcribed.
- related to →KMT2A / MLL1 — the gene that breaks
Counts reciprocal alleles across the whole KMT2A recombinome, not only t(4;11).
- expressed in →KMT2A-rearranged acute lymphoblastic leukaemia
94% of KMT2A rearrangements generate a reciprocal fusion gene; 4.6% of patients have only the reciprocal allele.
Supplies the denominator behind that entry's 'about half of patients' framing and corrects it upward at the DNA level.
Explains why the allele count and the transcript count differ by a factor of two.
- ← part ofAbout one KMT2A-rearranged patient in twenty has no direct fusion at all - only the reciprocal one
The 114/2454 figure is one row of that entry's frequency accounting.
Second partner family confirming that reciprocal products are the rule across the recombinome.
Records the laboratory concentration behind every frequency figure in this beat.