KMT2A minor breakpoint cluster region (BCR2): intron 20 - exon 24
also called KMT2A BCR2 · MLL minor BCR · 3' KMT2A breakpoint region
A small minority of KMT2A breaks (about 1 in 70) happen much further along the gene, past the chromatin-reading fingers. The fusion proteins these make are a different beast: they keep parts that every common KMT2A fusion throws away.
The same thing, for a scientist
A second, much rarer breakpoint cluster region spans KMT2A intron 20 to exon 24. Of 3401 genomically characterised KMT2A rearrangements, 47 (1.4%) fell in BCR2; in the targeted-NGS-only subset the share rises to ~6%, implying historical under-detection by LD-PCR [E1]. The partner spectrum is almost disjoint from the major BCR: USP2 (n=29), AFDN (n=9) and SEPTIN6 (n=3) account for ~85% of BCR2 cases, and USP2 and SEPTIN6 are found exclusively in BCR2, whereas the four commonest major-BCR partners (AFF1, MLLT1, MLLT3, MLLT10) account for ~80% of major-BCR cases [E1]. Phenotypically BCR2 is enriched for B-ALL and MPAL among USP2 cases and for T-ALL among AFDN cases [E1]. Functionally the key consequence is that a BCR2 break places the complete PHD1-3 cluster, the bromodomain and the complete ePHD4 into the direct fusion protein - modules that confer CYP33/PPIE binding, H3K4me2/3 reading and the ability to recruit a BMI1-containing Polycomb repressor complex to CXXC, i.e. the switch that converts KMT2A from activator to repressor [E1].
Why this is not a footnote1 deeper
The entire therapeutic and mechanistic literature on KMT2A fusions is built on major-BCR proteins: menin-binding N-terminus + CXXC + partner elongation module, with no chromatin reader. A minor-BCR fusion keeps PHD1-3 + bromodomain + ePHD4. Meyer et al. note explicitly that the PHD1-3/bromodomain unit exerts an important regulatory function when it binds the peptidyl-prolyl isomerase CYP33/PPIE, which enables recruitment of a Polycomb repressor complex to the CXXC domain and reverses KMT2A from a transcriptional activator into a repressor 1. A fusion protein that retains that switch is mechanistically a different molecule from KMT2A::AFF1, even though both are called 'KMT2A-rearranged' in the clinic.
The T-ALL connection
Nine KMT2A::AFDN and one KMT2A::USP2 breakpoint in the T-ALL cohort (n = 123) fell in the minor BCR 1. KMT2A-rearranged T-ALL is itself dominated by MLLT1 (n=43) and MLLT10 (n=40) 1; the AFDN minor-BCR cases are a small but molecularly distinct slice. This is one of the few places in the field where breakpoint position, not partner identity, plausibly drives lineage.
Partner spectrum, BCR2 vs BCR1
| Major BCR (BCR1) | Minor BCR (BCR2) | |
|---|---|---|
| n in DCAL cohort | 3336 (98%) | 47 (1.4%) |
| Top partners | AFF1, MLLT1, MLLT3, MLLT10 (~80%) | USP2 (29), AFDN (9), SEPTIN6 (3) (~85%) |
| Exclusive partners | - | USP2, SEPTIN6 |
| Phenotype | infant/paediatric/adult ALL and AML | USP2: mostly B-ALL (21) and MPAL (7), 1 AML. AFDN: mostly T-ALL (8), 1 B-ALL |
| PHD1-3 in direct fusion | lost | retained |
All numbers from the DCAL 3401-patient cohort 1. AML breakpoints occur nearly exclusively in BCR1 1.
| gene | KMT2A |
|---|---|
| cytoband | 11q23.3 |
| genome build | hg38 |
| region name | minor breakpoint cluster region (BCR2) |
| extent description | KMT2A intron 20 to exon 24 (Meyer/Marschalek DCAL exon numbering) |
| population | 3401 genomically characterised KMT2A-rearranged acute leukaemia patients (DCAL 2003-2022) |
| n cases | 47 |
| share of all kmt2a breaks PCT | 1.4 |
| share ngs subset PCT | 6 |
| functional consequence | Direct fusion retains the CYP33/PPIE-binding PHD3 and the H3K4me2/3 reader unit, hence retains the activator-to-repressor switch and BMI1/Polycomb recruitment capacity to CXXC |
| reciprocal product | Reciprocal partner::KMT2A products from BCR2 breaks carry only the far C-terminus of KMT2A |
| numbering convention | Meyer/Marschalek (DCAL) KMT2A exon numbering |
partner distribution — the numbers behind the chart
[
{
"partner": "USP2",
"n": 29,
"phenotype": "B-ALL (21), MPAL (7), AML (1)"
},
{
"partner": "AFDN",
"n": 9,
"phenotype": "T-ALL (8), B-ALL (1)"
},
{
"partner": "SEPTIN6",
"n": 3,
"phenotype": "ALL/MPAL"
}
]exclusive to bcr2
[ "USP2", "SEPTIN6" ]
domains retained 5 prime
[ "AT-hook 1-3", "SNL/repression region", "MBM1", "MBM2", "LEDGF/PSIP1-binding region", "CXXC", "PHD1", "PHD2", "ePHD3", "bromodomain", "ePHD4" ]
domains lost 5 prime
[ "FYRN", "FYRC", "TAD", "WIN motif", "SET" ]
- Minor-BCR fusions could be intrinsically menin-inhibitor resistant: if the retained PHD3-CYP33 axis can recruit Polycomb repressors to CXXC independently of menin, the fusion may hold its target loci without a menin bridge.
- Clinical trials that stratify only by partner gene (or only by FISH positivity) will silently mix PHD-retaining and PHD-lacking fusions, diluting any real efficacy signal and producing unexplained non-responders.
- Are minor-BCR fusion proteins menin-dependent at all? They retain MBM1/MBM2 so they should be, but they also retain the CYP33-responsive repressor switch, and nobody has tested a menin inhibitor against a KMT2A::USP2 or minor-BCR KMT2A::AFDN model.
- If targeted NGS really raises the minor-BCR share from 1.4% to ~6%, roughly 1 in 17 KMT2A-r patients may carry a PHD-retaining fusion. Is that subset systematically missing from menin-inhibitor trial cohorts, which enrol on the basis of FISH/karyotype?
- Why is USP2 (a deubiquitinase) exclusively a minor-BCR partner? Is this a splice-phase/reading-frame constraint or a functional selection?
- The 5' boundary of BCR2 is given as intron 19 by the 2019 founding report and intron 20 by the 2023 recombinome, same authors, neither commenting. Which is right determines whether a capture or MRD panel built from this entry covers all BCR2 breakpoints.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
A minor KMT2A breakpoint cluster region spans intron 20 to exon 24, accounts for 47/3401 (1.4%) of cases (~6% by NGS), is dominated by USP2, AFDN and SEPTIN6, and places the complete PHD1-3, bromodomain and ePHD4 into the direct fusion protein.
The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, et al. · Leukemia 2023What this evidence cannot show
n = 47 total minor-BCR cases, so all partner- and phenotype-specific counts are single- or low-double-digit. The BCR1:BCR2 ratio is method-dependent (98:1.4 overall vs 94:6 in the NGS subset), which means the true prevalence of BCR2 is uncertain and probably higher than 1.4%. No outcome data are reported for BCR2 cases as a group.
Evidence that argues against this (1)
- No independent cohort has been published that reproduces the BCR2 partner spectrum at comparable size, so the USP2 dominance could reflect referral bias at a single diagnostic centre rather than true biology. Meyer C et al. 2013
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Retention of PHD fingers in an MLL fusion protein suppresses transformation in murine progenitors, which is why minor-BCR fusions are mechanistically anomalous and require a different explanation for their leukaemogenicity.
The PHD fingers of MLL block MLL fusion protein-mediated transformation · Muntean AG, Giannola D, Udager AM, Hess JL · Blood 2008What this evidence cannot show
Murine retroviral system with MLL-AF9; minor-BCR partners in patients are USP2/AFDN/SEPTIN6, not AF9, so the comparison is indirect.
Evidence that argues against this (1)
- PHD fingers is too coarse a unit for this argument. When the individual fingers were tested, inserting PHD1 and PHD2 into MLL-ENL had NO effect on haematopoietic stem cell immortalisation; only the third PHD finger, alone or within the full cassette, blocked it, and it did so by recruiting CYP33 and HDAC1 and switching the fusion from transactivation to repression. A minor-BCR fusion is therefore anomalous specifically because it retains PHD3, which makes the anomaly sharper, not softer, than the PHD-fingers-block-transformation framing implies. Chen J et al. 2008
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Clustered PHD domains of KMT2A localise to H3K4me3- and H3-acetylation-rich active promoters and enhancers, and fusing the KMT2A CXXC domain to the PHDs sharply increases promoter preference - so a fusion that retains both CXXC and PHD1-3 has a chromatin-targeting logic unavailable to major-BCR fusions.
Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers · Stroynowska-Czerwinska AM, Klimczak M, Pastor M, et al. · Cellular and Molecular Life Sciences 2023What this evidence cannot show
Isolated-domain ChIP-type experiments in cell lines using engineered CXXC-PHD constructs, not patient-derived minor-BCR fusion proteins; extrapolation to KMT2A::USP2 or KMT2A::AFDN minor-BCR fusions is inference.
Evidence that argues against this (1)
- A CXXC-PHD construct that binds H3K4me3-rich promoters cannot be in the repressive mode at the same time, so the chromatin-targeting logic described here is only half the switch. Binding of H3K4me3 to PHD3 and binding of the CYP33 RRM to PHD3 are mutually inhibitory, and CYP33 engagement converts the same module into a repressor of HOXC8, HOXA9, CDKN1B and C-MYC. A promoter-preference assay measures the activating arm only; a BCR2 fusion retaining PHD3 in a CYP33-expressing cell could sit in the opposite state entirely. Park S et al. 2010
- E_founding_report_2019strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The founding report of this cluster is the 2019 description of recurrent MLL-USP2 fusions, which the entry did not cite. It places the region between KMT2A **intron 19** and exon 24 with a clear preference for introns 21-23, and supplies the ascertainment arithmetic the entry lacked: BCR2's 1.4% is its share of ALL KMT2A rearrangements, while among patients already known to be KMT2A-rearranged whose breakpoint MP-PCR and LDI-PCR could not find, BCR2 accounts for **21 of 93 (23%)**. The paper's title phrase 'a second breakpoint cluster region' means second IN TOTAL after the major BCR; it describes this cluster and not a third one.
Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions · Leukemia 2019What this evidence cannot show
Added by the coordinator on 2026-09-20, routed from a beat that does not own this file. The 5' boundary DISAGREES with the 2023 recombinome figure this entry currently states: 2019 says intron 19, 2023 says intron 20. Same authors and same centre, and neither publication comments on the change. Which is correct is unresolved here.
Evidence that argues against this (2)
- The one-intron discrepancy is not academic and resolving it matters more than either number. A capture or MRD panel designed from this entry's current intron-20 boundary would not cover intron 19 to 20 — in a genotype reported at 76% day-33 MRD positivity, where the breakpoint is the MRD target. Until the boundary is settled a panel should cover from intron 19. Leukemia 2019
- The 23% figure is the operationally useful one and is also the more selected: it is the yield among cases that two PCR methods already FAILED to resolve, so it describes what BCR2 contributes to a diagnostic residue rather than its share of the disease. Quoting it without that denominator would overstate BCR2 by roughly sixteen-fold. Leukemia 2019
- E_bcr2_not_partner_exclusivestrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The partner spectrum of BCR2 is nearly disjoint from the major BCR but NOT exclusive in both directions. USP2 and SEPTIN6 are confined to BCR2, and the converse does not hold: AFF1 (2 cases) and MLLT3 (1 case) also break within BCR2. KMT2A::USP2 is additionally an intrachromosomal INVERSION rather than a translocation, USP2 lying about 1 Mbp telomeric and transcribed toward the centromere.
Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions · Leukemia 2019What this evidence cannot show
Routed by the coordinator on 2026-09-20. The counts are small - 2 and 1 patients - so they establish that the exclusion fails rather than how often.
Evidence that argues against this (1)
- The inversion geometry matters for more than nomenclature. This graph's breakpoint entries and its fusion-lane viewer assume reciprocal translocation geometry, in which a reciprocal product exists on the partner chromosome. An intrachromosomal inversion produces a different reciprocal arrangement, so arguments in this project that turn on reciprocal presence or absence do not transfer to KMT2A::USP2 unexamined. Leukemia 2019
- related to →Lost from the KMT2A half: PHD3 and the bromodomain are one cassette, not two modules (aa 1566-1765)
Counter-evidence sharpening the minor-BCR anomaly: PHD1 and PHD2 inserted into MLL-ENL had NO effect on stem-cell immortalisation; only PHD3 blocked it (Chen 2008, PMID 18676843). A BCR2 fusion is anomalous specifically because it retains PHD3.
the second, minor breakpoint cluster region of the same gene; relevant to which fusions a PCR assay detects
- ← related toApoptotic nucleases cut KMT2A, and cells that survive the attempt can carry a translocation
any proposed break mechanism has to explain the position of both cluster regions, not just the major one
any proposed break mechanism has to explain the position of both cluster regions, not just the major one
- ← part ofKMT2A / MLL1 — the gene that breaks
1.4% by PCR, ~6% by targeted sequencing
SAME interval - this is the founding report of BCR2, not a third cluster; adds the intron 19 boundary and the 23% conditional ascertainment figure
USP2 breakpoints occur exclusively in BCR2
KMT2A break in BCR2 (intron 20 - exon 24), exclusively
- ← related toThe partner's deubiquitinase domain is what lets a PHD-retaining KMT2A fusion survive and transform
applies to every BCR2 fusion, because all of them retain PHD1-3 and the bromodomain
- ← part ofKMT2A::USP8, t(11;15)(q23;q21) - three patients, and the second instance of a deubiquitinase partner
one of four balanced translocations breaking in BCR2 in the discovery cohort
the class at risk: BCR2 fusions retain PHD1-3, the bromodomain and ePHD4, and are 1.4-6% of KMT2A-rearranged disease - too few to declare themselves in a trial-level response rate
SCORED AS MISSING THE QUALIFIER AND IS NOT: it says the true prevalence of BCR2 is uncertain and probably higher than 1.4%, which addresses the denominator better than the word the checker searched for.