C57BL/6-Tg(CD2-Tcra,-Tcrb)F8Mack/J

Stock number: 028304
Product name: Sur-TCR-Tg
Research areas: Cancer Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

Sur-TCR-Tg transgenic mice express a T cell receptor recognizing surivin, a tumor-associated antigen, during early stages of thymopoiesis.

Detailed description

These transgenic mice express a T cell receptor (TCR) recognizing an immunodominant epitope of mouse Survivin (Sur_20-28, a tumor-associated antigen (TAA)) during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) is reported to occur in 100% of Sur-TCR-Tg mice beginning at 4 months of age. T-ALL in Sur-TCR-Tg mice is characterized by enlargement of the spleen, thymus, lymph nodes, lung, liver, and kidney due to infiltration with sheets of terminal deoxynucleotidyl transferase (TdT)+ blasts. No phenotypic differences have been observed between hemizygotes and homozygotes. Both male and female transgenic mice are fertile. The transgene was integrated on mouse Chromosome 11, but copy number has not been determined.

The process of leukemogenesis observed in this model shows similarities with several other animal models of T-ALL, as well as T-ALL observed in patients treated with IL2Rγc-based gene therapy. In both this model and the clinical experience with IL2Rγc retroviral-based gene therapy, a receptor capable of providing a potent activation stimulus was expressed during the early stages of thymopoiesis and in both cases NOTCH1 mutations cooperated to generate full transformation. Although the issue of whether IL2Rγc expressed during early thymopoiesis can provide a leukemogenic signal is unresolved, several animal models have implicated the TCR as an oncogene in T-ALL. In some cases, TCR signaling during early thymopoiesis appears sufficient to induce T-ALL, whereas in others the TCR signals play a cooperating role as part of an oncogenic cascade. Pre-TCR signaling has also been implicated in T-ALL development as a cooperating event.

Development

Tcra (Vα8/Jα24/Cα) and Tcrb (Vβ13/Dβ2/Jβ2/Cβ2) cDNAs were amplified from Sur_20-28 tetramer binding CD8⁺ splenocytes and cloned into human CD2 minigene-based vectors. Sequence was introduced between (on the 5' end) the promoter, ATG-free first exon and first intron of the human CD2 gene and, on the 3' end ~500 bp of the 3' untranslated and flanking DNA of human CD2, including two polyadenylation signals and the 3' locus control region. The vectors were coinjected into fertilized C57BL/6N embryos. Resultant mice were maintained on a C57BL/6N background by the donating laboratory. The transgene was integrated on mouse Chromosome 11, but copy number has not been determined. This is founder line F8.

A 48 SNP (single nucleotide polymorphism) panel analysis, with 43 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. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 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 not on a C57BL/6N genetic background.

Allele

Symbol: Tg(CD2-Tcra,-Tcrb)F8Mack
Name: transgene insertion F8, Crystal Mackall
MGI accession ID: MGI:5784488
Generation method: Transgenic
Attributes: Inserted expressed sequence
Marker symbol: Tg(CD2-Tcra,-Tcrb)F8Mack
Marker name: transgene insertion F8, Crystal Mackall
Chromosome: 11
Strain of origin: C57BL/6
Expressed genes: Tcra,T cell receptor alpha chain,mouse, laboratory; Tcrb,T cell receptor beta chain,mouse, laboratory
Molecular note: Tcra (Valpha8/Jalpha24/Calpha) and Tcrb (Vbeta13/Dbeta2/Jbeta2/Cbeta2) cDNAs were amplified from Sur20-28 tetramer binding CD8+ splenocytes and cloned into human CD2 minigene-based vectors. Sequence was introduced between (on the 5' end) the promoter, ATG-free first exon and first intron of the human CD2 gene and, on the 3' end ~500 bp of the 3' untranslated and flanking DNA of human CD2, including two polyadenylation signals and the 3' locus control region. The two vectors were coinjected and three founders (E8, F8, L8) with a high frequency of Sur20-28 tetramer-binding CD8+ T cells were selected. The F8 transgene integrated on mouse Chromosome 11. Mice express a TCR with specificity for murine Birc5 (survivin) peptide (20-28) presented by H2.