A reciprocal-negative t(11;19) patient was documented in 1995 by a different mechanism entirely - the 3' half of KMT2A was simply deleted
also called 3' MLL deletion · cryptic t(11;19) T-ALL · Chervinsky 1995 case
Long before anyone described the spliced-fusion route, a T-cell leukaemia patient was found whose chromosome 11 had lost the second half of the KMT2A gene outright, so no mirror-image fusion could form. The authors concluded that the ordinary fusion, not the mirror image, was what caused the disease.
The same thing, for a scientist
A 1995 report described a T-ALL with a cytogenetically invisible t(11;19) in an apparently normal 46,XX karyotype. RT-PCR showed an in-frame MLL-ENL fusion mRNA, and *"MLL sequences distal (telomeric) to the breakpoint were deleted from the genome, which precludes the formation of a reciprocal ENL/MLL fusion protein."* The authors' stated conclusion was that *"an MLL/ENL fusion protein (and not a reciprocal ENL/MLL fusion) was likely to be pathogenic in this patient"* [E1]. This matters for the control-arm beat in three ways. It shows that reciprocal-negativity in this partner has at least **two** independent genomic causes, not one - upstream (spliced) breaks and 3' deletions - so a comparison built only on breakpoint position will misclassify some patients. It is the earliest explicit argument in the KMT2A literature that the direct product alone is sufficient. And it is a reciprocal-negative case in **T-lineage** disease, the lineage in which this fusion has its best outcomes, which is exactly the direction that would make lineage a confounder of any reciprocal-status comparison.
Why a 3' deletion is a cleaner negative than a spliced fusion
In a spliced fusion the 3' half of KMT2A survives on der(19) together with the gene-internal promoter upstream of exon 12, so a KMT2A* protein carrying the SET domain may still be expressed 2. In the 1995 case the distal MLL sequences were deleted from the genome, so there is no template for KMT2A* either 1. That makes genomic 3'-KMT2A deletion the only mechanism in this partner that is unambiguously free of both a reciprocal chimera and a C-terminal KMT2A fragment. It is also much rarer: the recombinome's complex-rearrangement analysis of 426 cases catalogues only two patients with a deletion of the 5'-KMT2A but with reciprocal fusion genes, and does not give a count for the converse 2.
The classification problem this creates for the control arm
The 241-versus-219 split rests on breakpoint position alone: upstream of MLLT1 exon 1 versus within MLLT1 2. Any patient in the '219' group who has also lost 3'-KMT2A sequence - by deletion, by an unbalanced three-way rearrangement, or by later clonal loss - is reciprocal-negative while being counted as reciprocal-positive. The direction of that misclassification is known (it moves negatives into the positive arm) and its size is not. A reciprocal-status comparison therefore needs a per-patient DNA or RNA assay for the reciprocal allele, not a breakpoint-derived label. This graph already holds concept-reciprocal-status-measured-by-dna-and-by-rna-disagree and mechanism-reciprocal-allele-loss-during-clonal-progression on the same point for other partners.
A cryptic translocation with a normal karyotype
The case had an apparently normal 46,XX karyotype and the rearrangement was found only because an MLL Southern rearrangement prompted cloning and FISH 1. Any historical cohort assembled by karyotype - which includes most of the t(11;19) outcome literature - is therefore ascertained against exactly this kind of case. That is an additional reason not to treat published t(11;19) series as an unbiased sample of the genomic classes this beat is trying to compare.
| mechanism | genomic deletion of 3'-KMT2A (telomeric to the breakpoint) |
|---|---|
| n cases | 1 |
| lineage | T-ALL |
| karyotype | 46,XX - translocation cytogenetically cryptic |
| reciprocal status | negative, and also KMT2A*-negative |
| year | 1995 |
| distinguishes from | spliced fusion, in which 3'-KMT2A survives on der(19) with its gene-internal promoter |
| consequence for control arm | reciprocal status cannot be inferred from breakpoint position alone; at least two genomic routes to reciprocal-negativity exist in this partner |
- If reciprocal status is used to stratify therapy, a breakpoint-based classifier will assign some genuinely reciprocal-negative patients to the reciprocal-positive arm, and the error is one-directional. A trial stratified that way would dilute a real effect rather than manufacture a false one - but it would also under-treat the misclassified patients if the arms receive different regimens.
- How often do KMT2A::MLLT1 patients with an intra-MLLT1 breakpoint nonetheless lack a reciprocal allele because 3'-KMT2A was deleted? The Frankfurt archive's genomic data would answer this directly and the number has never been reported for any partner.
- Was the 1995 patient's reciprocal allele lost at translocation or during clonal evolution? A deletion found at diagnosis cannot distinguish the two, and the distinction is the whole content of the hit-and-run model.
- Are cryptic t(11;19) cases systematically absent from the karyotype-based outcome series this field relies on, and if so does that bias the apparent good prognosis of T-lineage t(11;19)?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a patient with typical T-cell ALL (CD2+, CD4+, CD5+, CD7+, CD8+, HLA DR-) and an apparently normal 46,XX karyotype, an MLL gene rearrangement was cloned and a distal DNA fragment mapped by FISH to 19p13; RT-PCR demonstrated an in-frame fusion mRNA between the amino terminus of MLL and the carboxy terminus of ENL; MLL sequences distal (telomeric) to the breakpoint were deleted from the genome, which precludes the formation of a reciprocal ENL/MLL fusion protein; the authors concluded that the MLL/ENL fusion protein and not a reciprocal ENL/MLL fusion was likely pathogenic; and the report provided the first conclusive molecular evidence of an MLL/ENL gene fusion in T-cell ALL.
Complex MLL rearrangement in a patient with T-cell acute lymphoblastic leukemia. · Chervinsky DS, Sait SN, Nowak NJ, et al. · Genes Chromosomes Cancer 1995What this evidence cannot show
ABSTRACT ONLY. Europe PMC core returns pmcid null and isOpenAccess N, so routes 2-4 of the unreadable test have no PMCID; the body was not read. n = 1. The deletion was demonstrated by Southern and FISH mapping in 1995, methods that bound the deletion coarsely; a retained 3' fragment too small to see would change the interpretation. 'Precludes a reciprocal fusion protein' is the authors' inference from genomic structure, and no assay for a reciprocal transcript is described in the abstract. The pathogenicity conclusion is an argument from a single case, not an experiment.
Evidence that argues against this (1)
- The founding KMT2A paper reported that a t(11;19)-carrying cell line expresses fusion transcripts from both derivative chromosomes, so reciprocal expression does occur in this partner and the 1995 case is not representative of it. Tkachuk DC et al. 1992
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Read in full text (PMC10169636): about 50% of MLLT1 breakpoints (241 of 460) localise upstream of MLLT1 exon 1 and express only the direct transcript; of 426 complex KMT2A rearrangements analysed, 40 reciprocal fusions were in frame and 386 were non-functional or out of frame at the genomic DNA level, and the majority of the out-of-frame ones may still be transcribed and encode a 5'-truncated KMT2A protein, KMT2A*, from a gene-internal promoter upstream of KMT2A exon 12; the paper separately catalogues two patients with a deletion of the 5'-KMT2A but with reciprocal fusion genes.
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 (body element present). The paper gives no count of patients with 3'-KMT2A deletion in the MLLT1 group specifically, so the size of the misclassification described above is unmeasured and this entry does not estimate it.
Evidence that argues against this (1)
- The same paper's preferred framing is that reciprocal products are important early and dispensable later, so a patient who has lost the reciprocal allele by the time of diagnosis is not evidence that it was never needed. Meyer C et al. 2023
one documented leak in the reciprocal-positive arm
a reciprocal-negative t(11;19) case by 3'-KMT2A deletion, T-lineage
a human case in which the reciprocal allele is absent by genomic deletion