The most faithful mouse models of t(11;19) are reciprocal-positive by design, and the commonest ones carry no reciprocal allele at all - and nobody has compared them
also called Mll-Enl translocator mice · Cre-loxP interchromosomal recombination · retroviral MLL-ENL
There are two ways to give a mouse this fusion: engineer a real chromosome swap, which produces both the fusion and its mirror image, or insert the fusion gene alone, which produces only the fusion. Both are used, they give the leukaemia, and no one has ever put them side by side to ask whether the mirror image matters.
The same thing, for a scientist
Mouse modelling of MLL-ENL divides on exactly the axis this beat cares about, and the division is invisible because nobody frames it that way. **Reciprocal-positive:** developmentally regulated Cre-loxP-mediated interchromosomal recombination between *Mll* and *Enl* creates **reciprocal chromosomal translocations** that cause myeloid tumours, with rapid onset and high penetrance and translocation-bearing cells detectable in marrow by 12 days after birth [E1]; the same translocator system was used to restrict the translocation to different haematopoietic compartments, where Mll-Enl caused myeloid neoplasia from stem cells or progenitors but no tumours when restricted to B cells [E2]. **Reciprocal-negative:** every retroviral or lentiviral MLL-ENL transduction model - the standard system for colony replating and for the YEATS-domain work - delivers the direct fusion cDNA and nothing else [E3]. **The comparison has never been made.** A translocator mouse against a transduction mouse differs in far more than reciprocal status (locus, promoter, copy number, timing, cell of origin), so the existing literature does not accidentally contain the experiment either.
Why this is the cheapest reciprocal-status experiment available
The human comparison needs an archive, a data-sharing agreement and outcome linkage 4. The mouse comparison needs two constructs. Transduce lineage-negative marrow with MLL-ENL alone and, in parallel, with MLL-ENL plus ENL-MLL, and compare latency, leukemic stem cell frequency by limiting dilution, and menin-inhibitor sensitivity. The reciprocal construct does not exist - no MLLT1::KMT2A cDNA has been cloned 5 - which is the only real obstacle and is a cloning problem, not a discovery problem. The analogous constructs for AFF1::KMT2A and AFDN::KMT2A were built and used, and the resulting claim - that reciprocal products act as chromatin-opening complexes letting the direct fusion activate roughly tenfold more target genes - is the strongest evidence the reciprocal-remainder hypothesis has 6.
What the translocator mice do and do not show about the reciprocal product
They show that a genuine reciprocal t(11;19)-equivalent is leukaemogenic in mice with high penetrance 1. They do not show that the reciprocal allele contributes, because there is no reciprocal-negative arm: every animal in those experiments carries both derivatives. Neither abstract states whether the reciprocal Enl-Mll transcript is expressed, and neither paper's full text was reachable - Europe PMC returns no PMCID for either. So even the basic fact of whether these mice make a reciprocal transcript is, from the published record available here, unestablished.
The lineage result is the one that transfers
Mll-Enl translocations caused myeloid neoplasia when they occurred in haematopoietic stem cells or semi-committed progenitors and no tumours when restricted to the B-cell compartment, although the translocation occurred and Mll-Enl fusion mRNA was expressed there 2. In humans this fusion is 88% lymphoblastic 7. That is a real discordance between the mouse system and the human disease, and it means mouse MLL-ENL results are being generated in the minority phenotype - the same shape of problem as KOPN-8 carrying the minority architecture.
| comparison performed | false |
|---|---|
| blocking reagent | no cloned MLLT1::KMT2A (ENL-MLL) cDNA has been reported |
| phenotype discordance | mouse translocator Mll-Enl gives myeloid neoplasia and no tumours from B-restricted translocation; human KMT2A::MLLT1 is 404/460 ALL |
reciprocal positive models
[ "Cre-loxP Mll-Enl translocator mice (PMID 12781363)", "compartment-restricted Mll-Enl translocator mice (PMID 17906700)" ]
reciprocal negative models
[ "retroviral/MSCV MLL-ENL transduction of lineage-negative mouse marrow (standard; e.g. PMID 36435883, PMID 9418860)" ]
analogous reagents that exist
[ "AFF1::KMT2A", "AFDN::KMT2A" ]
- Preclinical efficacy for this fusion is generated almost entirely in reciprocal-negative, myeloid mouse models of a disease that is reciprocal-positive about a third of the time and lymphoblastic 88% of the time. If reciprocal status modifies drug response, the mouse package could not have detected it, and if lineage modifies it, the package is testing the wrong lineage.
- Do the Mll-Enl translocator mice express a reciprocal Enl-Mll transcript? Neither paper's abstract says, and neither full text was reachable, so the most basic fact about the only reciprocal-positive model is unrecorded here.
- Would co-expressing a reciprocal construct with MLL-ENL change latency or leukemic stem cell frequency? This is a two-arm transduction experiment whose only missing part is a cDNA.
- Why is mouse MLL-ENL myeloid when human KMT2A::MLLT1 is 88% lymphoblastic? The translocator paper answers 'cell of origin', but the B-restricted arm expressed the fusion and made no tumour, which is a stronger statement than a cell-of-origin preference.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Developmentally regulated Cre-loxP-mediated interchromosomal recombination between the Mll gene and the Enl gene creates reciprocal chromosomal translocations that cause myeloid tumours, with rapid onset and high penetrance of leukaemogenesis in these translocator mice and high proportions of cells carrying chromosomal translocations found in bone marrow as early as 12 days after birth.
Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer. · Forster A, Pannell R, Drynan LF, et al. · Cancer Cell 2003What this evidence cannot show
ABSTRACT ONLY. Europe PMC returns pmcid null and isOpenAccess N, so routes 2-4 of the unreadable test have no PMCID. The abstract says the translocations are reciprocal but does not state whether the reciprocal Enl-Mll transcript is expressed, and there is no reciprocal-negative comparator in the design.
Evidence that argues against this (1)
- Retroviral MLL-ENL, which carries no reciprocal allele, also transforms and causes leukaemia, so the reciprocal allele is plainly not necessary for the phenotype in mice. Hu H et al. 2023
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In translocator mice where reciprocal chromosomal translocations occur by Cre-loxP recombination in different haematopoietic compartments, translocations between Mll and Enl caused myeloid neoplasias initiating in stem cells or progenitors, while no tumours arose when the translocation was restricted to the B-cell compartment despite the translocation occurring and Mll-Enl fusion mRNA being expressed there.
Leukaemia lineage specification caused by cell-specific Mll-Enl translocations. · Cano F, Drynan LF, Pannell R, et al. · Oncogene 2008What this evidence cannot show
ABSTRACT ONLY; Europe PMC returns pmcid null and isOpenAccess N. Mouse B-cell development differs from human infant B-lymphopoiesis, and the human disease's dominant compartment is a fetal-liver-derived lympho-myeloid-primed progenitor that this system may not model. No reciprocal-negative comparator.
Evidence that argues against this (1)
- In humans this fusion is overwhelmingly lymphoid - 404 of 460 cases are ALL - so the mouse system's myeloid restriction is a departure from the disease rather than a description of it. Meyer C et al. 2023
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Read in full text (PMC11246743): MLL-ENL and MLL-ENL-delta-YEATS were studied by retroviral transduction of lineage-negative mouse bone marrow cells from 5-FU-treated C57Bl/6 mice followed by injection into lethally irradiated syngeneic recipients, with MSCV as vector control - a system that delivers the direct fusion cDNA alone.
The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia. · Hu H, Saha N, Yang Y, Ahmad E, et al. · Leukemia 2023What this evidence cannot show
Read via the PMC HTML page after fullTextXML returned HTTP 500. The paper does not discuss reciprocal alleles at all; the observation that its system is reciprocal-negative is this graph's reading of the methods, not a claim the paper makes.
Evidence that argues against this (1)
- Retroviral transduction also overexpresses the fusion from a viral LTR at non-physiological copy number, so 'reciprocal-negative' is one of several ways such a model departs from the patient and is not the most obvious one. Slany RK et al. 1998
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Read in full text (PMC11246743): the 302-patient t(11;19) breakpoint dataset was provided by R. Marschalek of the Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology, University of Frankfurt.
The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia. · Hu H, Saha N, Yang Y, Ahmad E, et al. · Leukemia 2023What this evidence cannot show
Read from the author-contributions statement on the PMC HTML page. The statement establishes provenance of the breakpoint data, not the existence of linked outcome data.
Evidence that argues against this (1)
- The recombinome states the database can be queried for specific cohorts and that the authors will share data with requesting scientists, so the access barrier may be lower than assumed. Meyer C et al. 2023
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The reciprocal product of t(11;19) was reported at transcript level in 1992 as fusion transcripts expressed from both derivative chromosomes in a t(11;19)-carrying cell line, and no cloned MLLT1::KMT2A cDNA, expression construct or antibody has been reported since.
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; no PMCID. The 'and nothing since' half is a bounded absence resting on the searches recorded in absence-no-kmt2a-mllt1-analysis-stratified-by-reciprocal-or-spliced-status, not on this citation.
Evidence that argues against this (1)
- Reagents can exist without a dedicated publication; an unpublished construct in the Marschalek or Cleary laboratories would not appear in any search performed here. Marschalek R 2020
- E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Read in full text (PMC10169636): recent studies with two reciprocal fusion proteins, AFF1::KMT2A and AFDN::KMT2A, demonstrated their function as chromatin-opening protein complexes which subsequently allowed the corresponding direct KMT2A fusion proteins to activate about tenfold more target 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. This is a review sentence summarising the same group's own primary work in transfected cells; the keystone chromatin experiment for AFF1::KMT2A was performed in HEK293T cells, which are not haematopoietic.
Evidence that argues against this (1)
- Removing the reciprocal transcript from human t(4;11) leukaemia lines produced no growth, cell-cycle or apoptotic phenotype, so whatever the chromatin-opening function does, an established leukaemia does not need it. Kumar AR et al. 2011
- E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Read in full text (PMC10169636), Table 1: of 460 KMT2A::MLLT1 cases, 404 are ALL, 47 are AML and 9 are other.
The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, et al. · Leukemia 2023What this evidence cannot show
Column totals are this graph's arithmetic on the twelve published cell counts. Referral series, not a population sample.
Evidence that argues against this (1)
- In paediatric AML cohorts assembled by karyotype this fusion is a recognised and substantial group (n = 56 of 1,256), so its rarity in AML is relative, not absolute. van Weelderen RE et al. 2024
the in vitro/in vivo counterpart of the human comparison, and it has never been run either
model systems for this fusion, split by reciprocal status
a two-arm transduction experiment blocked only by the absence of a cloned reciprocal cDNA
adds a transgenic MLL-ENL model that is reciprocal-negative by construction, with a neonatal initiation peak