KMT2A::MAPRE1 (MLL-EB1) - a coiled-coil dimerisation fusion from pro-B ALL with a mouse model, low leukaemogenic potential, and Ets1 as its effector
also called MLL-EB1 · KMT2A::MAPRE1 · MLL/EB1 · MLL-MAPRE1 · t(11;20)(q23;q11.2)
In one adult patient with pro-B acute lymphoblastic leukaemia, the KMT2A gene was joined to EB1, a gene for a microtubule-tip protein. The joined protein sits in the nucleus and can turn mouse bone marrow cancerous, but it does so weakly compared with other KMT2A fusions.
The same thing, for a scientist
KMT2A::MAPRE1 (MLL-EB1) was reported in a single adult pro-B ALL patient: MLL exon 6 fused in frame to EB1 exon 5, at 20q11.2, the first chromosome 20 partner found for MLL, with the reciprocal EB1-MLL transcript also verified. The genomic break junctions carry duplications, deletions, inversions and 2 bp non-template insertions, which the authors read as a DNA damage-repair origin rather than a clean reciprocal exchange. Immunofluorescence localises the fusion protein to nuclei. In a mouse retroviral transduction / bone marrow transplantation model, the EB1 coiled-coil four-helix bundle is required for immortalisation; MLL/EB1 immortalises marrow into MYELOID lines despite the index patient's lymphoid disease, has lower leukaemogenic ability than MLL/AF10 with slower growth, increased apoptosis and incompletely penetrant acute monocytic leukaemia, and selectively upregulates Ets1, whose knockdown reduces engraftment and prolongs survival. This places MAPRE1 in the dimerisation class of cytoplasmic KMT2A partners alongside GAS7, GPHN and the septins.
Why this fusion is worth an entry
It is a single-patient fusion, which usually would not merit one. Three things change that. First, it is in the index lineage - pro-B ALL - where most of the cytoplasmic coiled-coil partners this graph holds (GAS7, GPHN, the septins) come from myeloid disease. Second, it has a mouse model with a named effector, which most single-patient KMT2A partners do not. Third, it makes a clean comparator for the menin-interface hypothesis: a canonical-orientation fusion whose partner supplies nothing but oligomerisation, and which is measurably WEAKER than MLL/AF10. If menin engagement by the retained KMT2A N-terminus were sufficient, a pure dimerisation partner should not be weak 12.
What has never been done to it
| gene5 | KMT2A |
|---|---|
| gene3 | MAPRE1 |
| kmt2a partner | MAPRE1 / EB1 |
| partner uniprot | Q15691 |
| partner length AA | 268 |
| cytogenetics | MAPRE1 is at 20q11.2; MLL/KMT2A at 11q23. The break junctions are complex (multiple breaks, duplications, deletions, inversions, 2 bp non-template insertions), so a simple reciprocal-translocation nomenclature understates the event. |
| breakpoint | MLL exon 6 :: EB1 exon 5, in frame; reciprocal EB1-MLL also verified |
| orientation | Canonical leukaemogenic orientation - KMT2A 5', partner 3'. The KMT2A N-terminus (AT-hooks, CxxC, menin-binding motifs) is retained. |
| partner class | dimerisation / oligomerisation via a coiled-coil four-helix bundle, the same class as GAS7, GPHN and the septins |
| disease | adult pro-B acute lymphoblastic leukaemia (n = 1 published patient); the mouse model produces acute monocytic leukaemia |
| n published cases | 1 |
| fusion protein localisation | nuclei, by immunofluorescence (Fu 2005); no subnuclear resolution, no fractionation |
| effector | Ets1, selectively upregulated by MLL/EB1 relative to MLL/AF10; knockdown reduces engraftment and leukaemia incidence and prolongs survival |
| relative potency | LOWER than MLL/AF10 - slower growth, increased apoptosis, incomplete penetrance, longer survival |
| menin dependency | NEVER MEASURED. No menin inhibitor, no MEN1 knockdown and no MBM-mutant experiment has been run on MLL/EB1. |
| dot1l dependency | NEVER MEASURED. |
| absence class | never-measured |
| absence class note | Menin dependency, DOT1L dependency, occupancy, H3K79 status and any second patient are all never-measured for this fusion. GEO checked via the routes in the standing brief: no deposition is attributed to either paper's PMID. |
| graph context | No KMT2A::MAPRE1 node existed in this graph's 1,924 entries before this one, although fusion-kmt2a-gas7, fusion-kmt2a-gphn and four septin fusions - the same partner class - are all present. |
model systems
[ "mouse bone marrow retroviral transduction/transplantation (Fu 2019)" ]
- A single-patient fusion carries real risk of over-weighting: one report, one group, and no independent confirmation in twenty years.
- The mouse model produced myeloid disease from a lymphoid patient's fusion, so it cannot be used to argue anything about lineage.
- If MLL/EB1 turns out to be menin-INdependent, that is a problem for the menin-interface hypothesis and should be looked for, not away from.
- Is MLL/EB1 menin-dependent? A canonical-orientation fusion whose partner supplies only oligomerisation, and which is measurably weaker than MLL/AF10, is the cleanest available test of whether menin engagement alone is sufficient.
- Is Ets1 an MLL-fusion target in the index fusion KMT2A::AFF1, or only in MLL/EB1? The published comparison is against MLL/AF10.
- Why is this fusion weak? Lower potency in a fusion that retains the whole KMT2A N-terminus is informative about what the C-terminal partner contributes beyond dimerisation, and nobody has followed it up in twenty years.
- Has any second KMT2A::MAPRE1 case been sequenced and not reported? A query of a large fusion-calling cohort would be cheap.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In an adult patient with pro-B acute lymphoblastic leukaemia the EB1 (MAPRE1) gene at 20q11.2 is fused to MLL, with MLL exon 6 joined in frame to EB1 exon 5; both MLL-EB1 and reciprocal EB1-MLL transcripts were verified by RT-PCR, the genomic break junctions were sequenced and show multiple breaks with duplicated, deleted and inverted fragments and 2 bp non-template insertions, and immunofluorescence showed the MLL-EB1 fusion proteins localised in the nuclei.
MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia. · Fu JF, Hsu HC, Shih LY · Genes Chromosomes Cancer 2005What this evidence cannot show
n = 1 ADULT patient with pro-B ALL, not an infant. Southern blot, cDNA panhandle PCR, RT-PCR and long-distance PCR. The nuclear localisation is a single immunofluorescence result with no subnuclear resolution and no fractionation. The break-junction architecture is complex, so 't(11;20)(q23;q11.2)' understates what happened. Read from the abstract.
Evidence that argues against this (1)
- One patient is one patient. MAPRE1 does not appear in the standard KMT2A recombinome tallies this graph uses elsewhere, and no second case has been published in the twenty years since. The mouse work that follows produced a MYELOID disease from a lymphoid patient's fusion, which is the recurring lineage-transfer problem in this literature. Fu JF et al. 2019
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The coiled-coil four-helix bundle of EB1 within MLL/EB1 is required to immortalise mouse bone marrow cells, which produced myeloid but not lymphoid lines; MLL/EB1 has low leukaemogenic ability compared with MLL/AF10, growing more slowly with increased apoptosis and inducing acute monocytic leukaemia with incomplete penetrance and longer survival; Ets1 is selectively upregulated by MLL/EB1, and shRNA knockdown of Ets1 reduced CD115 expression, apoptosis rate, competitive engraftment to marrow and spleen and leukaemia incidence, and prolonged survival.
Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model. · Fu JF, Yen TH, Huang YJ, Shih LY · Neoplasia 2019What this evidence cannot show
MOUSE retroviral transduction / bone marrow transplantation. The disease modelled is MYELOID while the index patient was pro-B ALL, a lineage switch that must appear in any claim built on this (rule 73). Ets1 was selected from 318 genes differing at least two-fold between MLL/EB1 and MLL/AF10 cell lines; the comparator is MLL/AF10, not the index fusion KMT2A::AFF1. Read from the abstract.
Evidence that argues against this (1)
- A coiled-coil that supplies oligomerisation is interchangeable in principle, so this model may say more about dimerisation than about EB1. The same group's own framing - 'MLL fusion with the coiled-coil domain-containing partner genes' - treats EB1 as a representative of a class. Wild-type EB1's microtubule function plays no stated role in the mechanism, which is why the separate AP-MS finding that wild-type EB1 co-purifies with seven MLL fusions cannot be read as corroborating this fusion. Skucha A et al. 2018
MAPRE1/EB1 supplies the C-terminal coiled-coil four-helix bundle of the fusion; MLL exon 6 :: EB1 exon 5
- fuses with →KMT2A / MLL1 — the gene that breaks
MLL exon 6 fused in frame to EB1 exon 5 in adult pro-B ALL; reciprocal EB1-MLL also verified
- analogous to →KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class
same partner class - a cytoplasmic protein supplying a coiled-coil oligomerisation module - and both are weak relative to the elongation-complex fusions
- analogous to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
comparator for the menin-interface hypothesis: both retain the KMT2A N-terminus, but MAPRE1 supplies only dimerisation and is measurably less leukaemogenic than MLL/AF10, while AFF1 supplies the SEC
EB1 is a cytoplasmic partner like the septins and GPHN, yet the MLL-EB1 fusion protein is nuclear by IF (Fu 2005) - the same compartment question that entry frames
THE OTHER OPEN ARM, AND THE ONE THAT COULD FALSIFY THE CIS LIMB: MLL/EB1 retains the whole KMT2A N-terminus including the MBM, so both hypotheses predict menin sensitivity, yet it is measurably weaker than MLL/AF10. An MBM-bearing, menin-INSENSITIVE lesion would break the 'if and only if' in the MBM statement, and no menin inhibitor, MEN1 knockdown or MBM-mutant experiment has ever been run on it.