B6;129X1-Kmt2a^tm2Sjk/JjdhJ

Stock number: 021296
Research areas: Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

These Mll-Cbp^STOP mice may be useful when studying the role of the chromosomal translocation MLL-CBP t(11;16)(q23;p13) on therapy-induced myeloproliferative diseases.

Detailed description

These Mll-Cbp^STOP mice carry a floxed STOP cassette upstream of exon 8 of the myeloid/lymphoid or mixed-lineage leukemia 1 (Mll1) gene, and a CREB binding protein (Cbp) cDNA, a Simian virus 40 polyadenylation signal (SV40 pA), and a puromycin resistance sequence (puro) in Mll1 exon 8. Mice that are heterozygous for the targeted mutation are viable and fertile with no Mll-Cbp fusion protein expression detected. Homozygous mice are not viable. The MLL-CBP fusion protein is a characteristic of the t(11;16)(q23;p13) chromosomal translocation found in patients with therapy-induced myeloproliferative diseases, including acute myelomonocytic leukemia (t-AMML), chronic myelomonocytic leukemia (t-CMML), and myelodysplastic syndrome (t-MDS).

When bred to mice that express interferon-inducible Cre recombinase (see Stock No. 003556), resulting offspring treated with polyinosinic-polycytidylic acid (pI-pC) will have the floxed-STOP cassette deleted in the cre-expressing tissues. This allows the expression of the MLL-CBP in cre-expressing tissue. These mice exhibit a three-fold reduction in common lymphoid progenitors (CLPs) and a 3-fold increase in myeloid progenitors, with enhanced proliferation, in bone marrow. This myeloid hyperplasia is evident within days of MLL-CBP expression. Subsequent γ-irradiation or N-ethyl-N-nitrosourea (ENU) treatment results in the onset of a spectrum of myeloproliferative disease and decreased survival.

Development

A targeting vector was designed to insert a loxP-flanked stop cassette upstream of exon 8 of the myeloid/lymphoid or mixed-lineage leukemia 1 (Mll1) gene. A cassette containing 6.5-kb fragment of murine CREB binding protein (Cbp) cDNA, a Simian virus 40 polyadenylation signal (SV40 pA), and a puromycin resistance sequence (puro) was inserted into Mll1 exon 8. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimeric males were bred to C57BL/6 females. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Allele

Symbol: Kmt2a^tm2Sjk
Name: targeted mutation 2, Stanley J Korsmeyer
MGI accession ID: MGI:3528758
Generation method: Targeted
Attributes: Inserted expressed sequence
Marker symbol: Kmt2a
Marker name: lysine (K)-specific methyltransferase 2A
Chromosome: 9
Strain of origin: 129X1/SvJ
Expressed genes: Crebbp,CREB binding protein,mouse, laboratory; Kmt2a,lysine (K)-specific methyltransferase 2A,mouse, laboratory
Site of expression: A Kmt2a-Crebbp (Mll-Cbp) fusion protein is expressed in cre-expressing tissues after these mice are bred with mice carrying cre recombinase.
Molecular note: A targeting vector was designed to insert a loxP-flanked stop cassette upstream of exon 8 of the lysine (K)-specific methyltransferase 2A (Kmt2a) gene. A cassette containing 6.5-kb fragment of murine CREB binding protein (Cbp) cDNA, a Simian virus 40 polyadenylation signal (SV40 pA), and a puromycin resistance sequence (puro) was inserted into exon 8.