t(6;11) makes four fusion genes, not two, and the PHD/bromodomain cassette is what opens chromatin in all of them
also called AF6-MLL · AFDN-KMT2A reciprocal · exMLL-AF6 · AF6-shMLL
A different chromosome swap, involving a gene called AFDN, turns out to make four hybrid genes depending on where the break falls. The ones carrying a particular reading module switch on huge numbers of genes across the whole genome.
The same thing, for a scientist
t(6;11)(q27;q23) patients divide by KMT2A breakpoint: the major cluster region (introns 9-10) is associated mainly with AML M1/M4/M5, and the minor cluster region (introns 21-23) with T-ALL. All four resulting fusion genes - MLL-AF6, AF6-MLL, exMLL-AF6 and AF6-shMLL - were cloned and expressed in a doxycycline-inducible system, and differential expression measured by MACE-Seq [E1]. The conclusion is a domain attribution rather than a fusion attribution: **the PHD/bromodomain cassette, present in the AF6-MLL and exMLL-AF6 proteins, is responsible for genome-wide chromatin activation**, producing strong deregulation of protein-coding genes, pseudogenes, non-annotated genes, lincRNAs and microRNAs [E1]. Cooperation between MLL-AF6 and AF6-MLL appears required for those effects, while exMLL-AF6 causes similar effects on its own; the exMLL-AF6 / AF6-shMLL pair induced myeloid and T-cell gene signatures together, offering an explanation for the T-ALL phenotype of minor-cluster patients [E1]. Two consequences for this beat. First, the reciprocal-product story is not t(4;11)-specific: the same laboratory reports the same architecture and the same chromatin-opening mechanism in a second partner family. Second, the causal element nominated is a **KMT2A domain cassette (PHD1-4 plus bromodomain)** that sits in the reciprocal product of every balanced KMT2A translocation, which makes it a general prediction rather than a partner-specific observation.
Why the minor cluster region matters here
Most of this graph's breakpoint material concerns the major cluster region, because that is where infant ALL breaks. t(6;11) with breaks in introns 21-23 produces an 'exMLL' fusion carrying far more of KMT2A - and a reciprocal 'shMLL' product carrying far less - and that configuration is associated with T-ALL rather than AML 1. Breakpoint position changing disease lineage, through the same partner gene, is about as direct an argument as exists that the amount of KMT2A in each product is a phenotype-determining variable.
What this entry is not
It is not evidence that the AFDN reciprocal product is expressed in patients at any particular frequency - that number is not in the abstract and this beat did not find it. It is not evidence of leukaemogenicity: the readout is differential gene expression in an inducible cell model, with the same non-haematopoietic-system caveat as the companion t(4;11) study. And the four-construct design means each individual attribution rests on one cell line per genotype.
| translocation | t(6;11)(q27;q23) |
|---|---|
| partner | AFDN (AF6) |
| major cluster introns | 9-10 |
| major cluster disease | AML M1/M4/M5 |
| minor cluster introns | 21-23 |
| minor cluster disease | T-ALL |
| causal element nominated | PHD/bromodomain cassette (KMT2A PHD1-4 1431-1978, bromodomain 1635-1765) |
| patient frequency of reciprocal expression | not reported |
fusion genes generated
[ "MLL-AF6", "AF6-MLL", "exMLL-AF6", "AF6-shMLL" ]
- If the PHD/bromodomain cassette is what opens chromatin, then the therapeutic target is a module present in wild-type KMT2A and in KMT2B, KMT2C and KMT2D - no selectivity is available from the domain itself.
- A menin inhibitor engages the direct product in major-cluster t(6;11) and is blind to the reciprocal one that this work nominates as the chromatin opener.
- What fraction of t(6;11) patients express the AF6-MLL reciprocal transcript? The frequency question answered for t(4;11) has not been asked here.
- Would deleting the PHD/bromodomain cassette from the reciprocal construct abolish the chromatin-opening effect? That is the mutation the domain attribution needs and it has not been made.
- Does the minor-cluster configuration exist in t(4;11)? If it does, some t(4;11) patients would have the PHD/bromodomain cassette in their DIRECT product - a menin-binding fusion that also reads H3K4me3.
- Is there a t(6;11) cell line in which the reciprocal transcript could be knocked down, as was done in t(4;11)?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
t(6;11)(q27;q23) patients divide into major breakpoint cluster region cases (MLL introns 9-10, mainly AML M1/M4/M5) and minor cluster region cases (introns 21-23, associated with T-ALL); all four resulting fusion genes MLL-AF6, AF6-MLL, exMLL-AF6 and AF6-shMLL were cloned into doxycycline-inducible stable cell models and profiled by MACE-Seq; the PHD/bromodomain cassette present in AF6-MLL and exMLL-AF6 is responsible for genome-wide chromatin activation, deregulating protein-coding genes, pseudogenes, non-annotated genes, lincRNAs and microRNAs; cooperation between MLL-AF6 and AF6-MLL appears required for these effects while exMLL-AF6 causes similar effects alone; and the exMLL-AF6 / AF6-shMLL co-expressing line displayed both a myeloid-specific and a T-cell-specific gene signature.
The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11). · Kundu A, Kowarz E, Marschalek R · Oncogene 2021What this evidence cannot show
An inducible transfected cell-model system with 48-hour induction and a 3'-end RNA-Seq readout; no leukaemia, no primary patient material, and the domain attribution is by comparison across constructs rather than by mutating the PHD/bromodomain cassette. Same laboratory and same experimental template as the t(4;11) companion study, so the two are not independent.
Evidence that argues against this (1)
- The direct counterpart claim in t(4;11) - that the reciprocal product matters - is contradicted by siRNA removal of the reciprocal transcript from human t(4;11) lines, which produced no phenotype, and no equivalent knockdown has been attempted in a t(6;11) line. Kumar AR et al. 2011
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Across the KMT2A recombinome, balanced translocations account for about 70% of rearrangements and a reciprocal fusion gene is generated in 94% of cases, so a reciprocal product is the rule rather than a t(4;11) peculiarity.
The reciprocal world of MLL fusions: A personal view. · Marschalek R · Biochim Biophys Acta Gene Regul Mech 2020What this evidence cannot show
Single-centre referral series presented as a personal view; counts alleles detectable by that centre's panel, not proteins.
Evidence that argues against this (1)
- Partner-specific geometry breaks the rule in at least one common family: about half of KMT2A::MLLT1 cases break upstream of MLLT1 exon 1 and produce no reciprocal transcript. Meyer C et al. 2023
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q03164 places PHD-type zinc fingers 1-4 at 1431-1482, 1479-1533, 1566-1627 and 1931-1978 and the bromodomain at 1635-1765 - all downstream of the major breakpoint cluster region and therefore in the reciprocal product of any major-cluster balanced translocation.
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. The inference that this cassette is in every major-cluster reciprocal product follows from breakpoint location, not from a UniProt statement, and does not hold for minor-cluster breaks in introns 21-23, which fall downstream of the cassette.
Evidence that argues against this (1)
- For minor breakpoint cluster region translocations the arithmetic inverts - the PHD/bromodomain cassette ends up in the DIRECT product and the reciprocal product is short - which is exactly the exMLL/shMLL configuration reported in t(6;11). Kundu A et al. 2021
same class of product in t(6;11)
- related to →KMT2A::AFDN (MLL-AF6), t(6;11)(q27;q23)
Describes the reciprocal and extended products of the same translocation.
Same architecture and same proposed chromatin-opening mechanism in a second KMT2A partner family.
- part of →KMT2A / MLL1 — the gene that breaks
Nominates the KMT2A PHD/bromodomain cassette as the causal element in reciprocal products generally.
Second partner family confirming that reciprocal products are the rule across the recombinome.
- ← analogous tot(9;11): the reciprocal product is made, is engineered into every genome-editing model, and has never been separately tested
Third partner family in the same reciprocal-product survey.