The reciprocal MLLT1::KMT2A transcript was reported in the paper that discovered KMT2A, and nobody has gone back to it in thirty-four years
also called ENL-MLL · ENL/MLL · der(19) transcript · reciprocal MLL-ENL · MLLT1-KMT2A
The 1992 paper that first identified the KMT2A gene noted that the t(11;19) cell line it studied made fusion messages from both broken chromosomes, not just one. In the three decades since, the mirror-image product of this translocation has never been cloned, expressed or tested.
The same thing, for a scientist
Tkachuk, Kohler and Cleary reported in Cell in 1992 that *"in a t(11;19)-carrying cell line fusion transcripts are expressed from both derivative chromosomes"*, with the der(11) transcript the more abundant of the two [E1]. That is a direct observation of a reciprocal MLLT1::KMT2A transcript, made in the founding paper of this entire field. Since then the reciprocal products of t(4;11) (AFF1::KMT2A) and t(6;11) (AFDN::KMT2A) have each been cloned, expressed and given functional characterisation, and the reciprocal product of t(11;19) has not. There is no published MLLT1::KMT2A cDNA clone, no antibody, no expression construct, no transformation assay and no knockdown. What the protein would contain is nevertheless derivable from gene geometry and UniProt coordinates, and the answer is pointed: it carries the KMT2A **WIN motif and SET domain** and **not** the menin-binding motif - the exact inverse of the direct fusion's targeting complement [E2].
What the reciprocal product would contain
This is an inference from gene geometry plus UniProt coordinates, not a measured protein; no MLLT1::KMT2A species has ever been detected at the protein level. A balanced t(11;19) with a KMT2A intron 11 break places KMT2A exons 12-37 on der(19). By UniProt Q03164 coordinates that fragment contains PHD1 (1431-1482), PHD2 (1479-1533), PHD3 (1566-1627), the bromodomain (1635-1765), the pre-PHD C2HC finger (1870-1910), PHD4 (1931-1978), FYRN (2018-2074), the 9aaTAD (2847-2855), FYRC (3666-3747), the WIN motif (3762-3767), the SET domain (3829-3945) and post-SET (3953-3969) 2. It does not contain the menin-binding motif (6-25), the LEDGF integrase-binding motifs (123-134, 147-152), the A.T hooks or the CXXC finger - all of which went to the direct fusion. So the reciprocal MLLT1::KMT2A is, like KMT2A*, a menin-blind and LEDGF-blind species that nonetheless carries the complete H3K4 methyltransferase module and its WDR5 docking motif. On the MLLT1 side it carries only whatever lies 5' of the direct fusion's junction: for the common exon-2 junction that is MLLT1 exon 1 alone, a fragment of the YEATS domain; for an exon-6 or exon-7 junction it is most of the YEATS reader 3.
Why the menin question turns on this
A menin inhibitor acts on the direct fusion, which carries the menin-binding motif. The reciprocal product does not carry that motif, so it is untouched by the drug by construction. In the reciprocal-positive half of the KMT2A::MLLT1 population - roughly 219 of 460 patients - a menin inhibitor therefore leaves behind a WIN-and-SET-bearing chromatin enzyme that the drug cannot reach, while in the reciprocal-negative half there is nothing left behind. That is the sharpest available version of the graph's standing concern that menin-inhibitor pharmacodynamics may be reporting on a subgroup rather than a mechanism, and it is testable in this partner without confounding by partner gene 4.
The state of the evidence, honestly
One sentence in one 1992 abstract is thin ground for a whole arm of a hypothesis. The Cell 1992 record has no PMCID in Europe PMC and is not open access, so the body of the paper - which cell line, which primers, whether the der(19) transcript was sequenced or only detected - was not read; all four PMC routes fail for want of a PMCID. What can be stated is what the fetched abstract says, and what Cellosaurus attributes: the KMT2A-MLLT1 fusion of the line HB11;19 (CVCL_8227) is referenced to exactly this paper 5. Whether HB11;19 is the line in which both transcripts were seen is a reasonable reading of the two records together and is not something either record states outright.
| reciprocal product | MLLT1::KMT2A (ENL-MLL), der(19) |
|---|---|
| first observation | transcript level, Cell 1992, PMID 1423624 |
| cloned | false |
| expressed construct | false |
| antibody | false |
| knockdown or knockout | false |
| menin binding | absent by construction - the menin-binding motif at KMT2A 6-25 goes to the direct fusion |
predicted retained kmt2a modules
[ "PHD1", "PHD2", "PHD3", "Bromodomain", "pre-PHD C2HC zinc finger", "PHD4", "FYRN", "TAD", "FYRC", "WIN", "SET" ]
predicted lost kmt2a modules
[ "MBM1", "IBM1", "IBM2", "AT-hook 1", "AT-hook 2", "AT-hook 3", "CXXC" ]
arm sizes — the numbers behind the chart
{
"reciprocal_negative_spliced": 241,
"reciprocal_capable_balanced": 219,
"total": 460
}- A menin inhibitor cannot bind the reciprocal product, because the reciprocal product does not carry a menin-binding motif. If the reciprocal product contributes to the leukaemic programme, menin inhibition in the reciprocal-positive half of this population is partial by construction and would look like partner-independent resistance.
- The WIN motif and SET domain retained on the predicted reciprocal product are the same modules a WDR5 or SET inhibitor would target, so combination strategies aimed at them would act only in the reciprocal-positive subgroup and would be diluted to non-significance in an unstratified trial.
- Is the MLLT1::KMT2A transcript of 1992 translated? Thirty-four years on there is no antibody, no construct and no mass-spectrometric identification, and a transcript seen once in one line is not a protein.
- Does MLLT1::KMT2A behave like AFF1::KMT2A and AFDN::KMT2A - the two reciprocal products that have been shown to act as chromatin-opening complexes that let the direct fusion activate roughly tenfold more target genes - or does the near-complete absence of partner-derived sequence in a t(11;19) reciprocal product make it a different kind of molecule?
- If the reciprocal product carries WIN and SET but not the menin motif, does a menin inhibitor leave the reciprocal-positive half of this population with an unaddressed chromatin enzyme? A WIN-motif inhibitor plus a menin inhibitor would be the pharmacological test, and it has never been run stratified by reciprocal status.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In the paper that identified KMT2A (then HRX) as a human trithorax homolog disrupted by 11q23 translocations, the authors state that in a t(11;19)-carrying cell line fusion transcripts are expressed from both derivative chromosomes, and that the more abundant derivative 11 transcript codes for a chimeric protein containing the AT hook motifs fused to a previously undescribed chromosome 19 protein they name ENL.
Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. · Tkachuk DC, Kohler S, Cleary ML · Cell 1992What this evidence cannot show
ABSTRACT ONLY. Europe PMC core returns pmcid null and isOpenAccess N for this record, so routes 2-4 of the unreadable test have no PMCID to use; the body was not read. The abstract does not name the cell line, does not say the der(19) transcript was sequenced, and does not say it was translated. A transcript detected by Northern or RT-PCR in 1992 is not a demonstration that a reciprocal protein exists.
Evidence that argues against this (1)
- A 1995 T-ALL case carried a t(11;19) in which the 3' KMT2A sequences were deleted from the genome, precluding any reciprocal ENL/MLL product, and the authors concluded the direct fusion and not the reciprocal was pathogenic - so reciprocal expression is neither universal nor necessary in this partner. Chervinsky DS et al. 1995
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q03164 (KMT2A_HUMAN, primary gene name KMT2A, 3969 aa) places the menin-binding motif at 6-25 and the integrase-binding motifs at 123-134 and 147-152, all 5' of an intron-11 breakpoint, while the WIN motif (3762-3767), the SET domain (3829-3945) and post-SET (3953-3969) lie 3' of it.
UniProtKB entry Q03164 (KMT2A_HUMAN), Histone-lysine N-methyltransferase 2A · UniProt Consortium · UniProtKB/Swiss-Prot 2026What this evidence cannot show
Fetched 2026-09-19; primary gene name and length read back. Mapping exon numbers onto residue coordinates is our inference from the position of the annotated domains relative to the published intron-11 breakpoint, not a coordinate published for the reciprocal product. A domain present in the sequence of a chimera is not thereby a folded, functional domain in that chimera.
Evidence that argues against this (1)
- The recombinome reports that a break within or downstream of KMT2A exon 11 - the position MLLT1 prefers - appears to leave PHD domain I misfolded on the reciprocal product, so the PHD fingers listed as retained may not be functional in exactly the cases where a reciprocal product exists for this partner. Meyer C et al. 2023
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
MLL/ENL fusion transcripts use ENL breakpoints at exons 2, 4, 6 or 7, all in frame, so the amount of MLLT1 sequence available to a reciprocal product varies from a single exon to most of the YEATS domain.
Analysis of acute leukemias with MLL/ENL fusion transcripts: identification of two novel breakpoints in ENL. · Fu JF, Liang DC, Shih LY · Am J Clin Pathol 2007What this evidence cannot show
Abstract-level reading; n = 15. The inference that the reciprocal product carries the complementary MLLT1 fragment is geometry, and this paper measured only direct transcripts.
Evidence that argues against this (1)
- In the largest genomic series, about half of all MLLT1 breakpoints lie upstream of MLLT1 exon 1, in which case no MLLT1 coding sequence reaches the reciprocal derivative at all and the geometry above does not apply. Meyer C et al. 2023
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Of 460 KMT2A::MLLT1 cases in the 3,401-patient recombinome, about 50% (n = 241) have breakpoints upstream of MLLT1 exon 1 and express only the direct fusion transcript and no reciprocal one, leaving roughly 219 cases in which a reciprocal allele can exist.
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. The 219 figure is 460 minus 241 and is this graph's arithmetic; the paper does not state it. 'Can exist' is not 'does exist': a balanced break still needs an in-frame junction and a transcribed allele, and the same paper's complex-rearrangement analysis found 386 of 426 reciprocal fusions out of frame or non-functional at the DNA level.
Evidence that argues against this (1)
- In t(4;11), reciprocal-expressing patients had markedly better event-free and overall survival, which is the opposite of what one would predict if the reciprocal product were an additional oncogenic burden left behind by a menin inhibitor. Agraz-Doblas A et al. 2019
- E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Cellosaurus accession CVCL_8227 (HB11;19) records a KMT2A + MLLT1 gene fusion named KMT2A-MLLT1 / MLL-MLLT1 / MLL-ENL, referenced to PubMed 1423624 and PubMed 16523483 and to DepMap ACH-001736.
Cellosaurus cell line HB11;19 (CVCL_8227) · Bairoch A, et al.; Cellosaurus · Cellosaurus (SIB) 2026What this evidence cannot show
Fetched 2026-09-19 by accession and the primary name was read back as HB11;19. Cellosaurus records the line's sex and age at derivation as unspecified. A database citing a paper for a fusion does not establish that the paper's reciprocal-transcript observation was made in that same line.
Evidence that argues against this (1)
- PubMed returns zero records for the queries 'HB1119' and 'HB-1119', so literature on this line is not reachable by its own name in PubMed and a counted absence of studies on it would be an artefact of indexing. Bairoch A et al. 2026
the der(19) product of t(11;19)
same class of product in t(4;11), where it has been cloned and characterised
- analogous to →t(6;11) makes four fusion genes, not two, and the PHD/bromodomain cassette is what opens chromatin in all of them
same class of product in t(6;11)
predicted: the reciprocal product retains the WIN motif (KMT2A 3762-3767) that docks WDR5
a reciprocal transcript for this partner has been directly observed, in 1992
- ← supportsThe KMT2A::MLLT1 chimeric protein: exactly what survives the join on each side, in residue numbers
supplies the residue coordinates from which the reciprocal product's contents are derived
the line in which both derivative transcripts were reported