C57BL/6-Bcr^{tm1(BCR/ABL)Tsr}/J

Stock number: 023520
Research areas: Cancer Research, Research Tools

Description

These conditional knock-in/knockout mice constitutively express a single copy of the human BCR/ABL p210-IRES-EGFP oncogene from the endogenous mouse Bcr locus after the excision of a loxP-flanked Stop cassette. Crosses with hematopoietic-specific cre lines produce animals that develop the earliest stages of CML, but not leukemia.

Detailed description

The BCR/ABL oncogene, associated with the t(9;22) Philadelphia chromosome in humans, is characteristic of chronic myeloid leukemia (CML).

These conditional knock-in/knockout mice constitutively express a single copy of the human BCR/ABL p210-IRES-EGFP from the endogenous mouse Bcr locus after the excision of a loxP-flanked Stop cassette. Heterozygous mice are born at predicted Mendlian frequency and display normal growth. Lack of expression of wildtype Bcr results in haploinsufficiency reflected in reduced message and protein.

Progeny derived from a cross with Vav1-cre (e.g. Stock No. 008610) or Mx1-cre (e.g. Stock No. 003556) mice to excise the floxed stop in hematopoietic cells develop the earliest stages of CML, but not leukemia, even when maintained for up to 1.5 years. This contrasts with previous models involving non-Bcr promoters and multiple copies of BCR/ABL. Compound mutant mice have normal white blood cell counts and their differentials display normal myeloid and monocytic frequencies, with only a slight trend of decreased lymphocyte frequencies over the first year of observation. White blood cells and spleen extracts in the compound mutant mice express GFP.

Development

Human BCR/ABL p210-IRES-EGFP cDNA and an Frt-flanked neomycin cassette were introduced to exon 1 of the mouse Bcr gene downstream of a loxP-flanked Stop cassette via homologous recombination in C57BL/6-derived embryonic stem (ES) cells. This strain was maintained on a C57BL/6 genetic background by the donating laboratory (see SNP note below).

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. One of the 27 markers throughout the genome was segregating, and 2 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Allele

Symbol: Bcr^{tm1(BCR/ABL)Tsr}
Name: targeted mutation 1, Theodora S Ross
MGI accession ID: MGI:5524984
Generation method: Targeted
Marker symbol: Bcr
Marker name: breakpoint cluster region
Chromosome: 10
Strain of origin: C57BL/6
Expressed genes: BCR/ABL,BCR/ABL fusion protein,human; GFP,Green Fluorescent Protein,
Site of expression: After the excision of the loxP-flanked Stop cassette, GFP is expressed in white blood cells and spleen extracts.
Molecular note: Human BCR/ABL p210-IRES-EGFP cDNA and an Frt-flanked neomycin cassette were introduced to exon 1 of the mouse Bcr gene downstream of a loxP-flanked Stop cassette via homologous recombination.