A bcr-v-abl oncogene induces lymphomas in transgenic mice.

Abstract

In chronic myeloid leukemia and some cases of acute lymphoblastic leukemia, a 9;22 chromosome translocation has fused most of the c-abl oncogene to a gene designated bcr. To explore in vivo the biological effects of the chimeric gene, we introduced a facsimile of the translocation product, a bcr-v-abl gene, into the mouse germ line under the control of the immunoglobulin heavy-chain enhancer or a retroviral long terminal repeat. Some transgenic mice bearing either construct developed clonal lymphoid tumors. T lymphomas predominated, but some pre-B lymphomas developed. The transgenes were expressed in the tumors but not detectably in the lymphoid tissues of nontumorous transgenic animals, implying that transcription is activated by a low-frequency somatic event. These results demonstrate that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis.

Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation

“…M1 cells were co-transfected with the MPZen(bcr ± abl) provirus (Hariharan et al, 1988) and a puromycin resistance plasmid to obtain M1 cell lines stably expressing BCR ± ABL. The MPZen(bcr ± abl) provirus incorporates the BCR ± ABL cDNA cloned from the human CML cell line K562 and encodes the 210 kD form of the BCR ± ABL protein.…”

The CD2-scl transgene alters the phenotype and frequency of T-lymphomas in N-ras transgenic or p53 deficient mice

“…Southern blots of HindIII or EcoRI digested DNA (10 mg) were hybridized with a 32 Plabelled 2 kb EcoRI fragment encompassing the TCR Jb2 region or a 670 bp PstI ± NaeI fragment spanning the J H4 region of the Igh gene (Hariharan et al, 1989). RNA was extracted with 4M guanidine thiocyanate and the polyadenylated fraction puri®ed by oligo(dT)-cellulose chromatography (Alexander et al, 1995).…”

Models of chronic myeloid leukemia

“…The first BCR/ABL transgenic mice expressed a BCR/vabl facsimile oncogene (similar to p210 BCR/ABL) under the immunoglobulin heavy-chain enhancer (Eµ) or the widely expressed promoter/enhancer from the long terminal repeat (LTR) of the murine myeloproliferative sarcoma virus (MPSV) [15]. There was a decreased yield of transgenic offspring from eggs injected with either transgene DNA, but a small number of transgenic founders of both types, and some progeny developed clonal T and B lymphomas.…”

“…Activated ABL genes are known to have cytotoxic effects, and the presence of the transgene in all tissues raises the possibility of toxicity during embryonic development. Toxicity was initially suggested by the inefficient generation of BCR/v-abl transgenic founders and the failure of this transgene to express prior to development of overt malignancy [15], whereas a subsequent study directly confirmed that a BCR/ABL transgene expressed from the BCR promoter caused embryonic lethality [30]. The δMT-1 promoter should be expressed in myeloid progenitors, but this promoter may be downregulated in these transgenic mice because of transgene toxicity, and the resulting low levels of BCR/ABL expression are below a threshold required for oncogenic transformation by tyrosine kinases.…”