Perturbation of B and T cell development and predisposition to lymphomagenesis in EμBmi1 transgenic mice require the Bmi1 RING finger

Abstract

Proviral activation of the Bmi1 gene has implicated Bmi1 as a collaborator of c-Myc in lymphomagenesis. To determine the eect of Bmi1 overexpression on hematopoiesis and lymphomagenesis transgenic mice were generated that overexpress dierent forms of the Bmi1 protein in their lymphoid compartment. EmBmi1 transgenic mice, overexpressing the wild type Bmi1 protein showed a perturbed lymphoid development and were highly susceptible to B and T cell lymphomagenesis. Mutational analysis of the Bmi1 protein demonstrated that the conserved N-terminal RING ®nger and central part of Bmi1 are essential for its oncogenic potential whereas the C-terminal Pro-Ser rich region is not required. We have used provirus tagging in the EmBmi1 mice to identify genes that cooperate with Bmi1 in lymphomagenesis. MoMLV infection in EmBmi1 transgenic mice accelerated lymphoma development. Proviral activation of the Pim and Myc genes but not the G®1 gene were frequently observed in these tumors. These results demonstrate that Bmi1 is a potent oncogene and suggest that it plays an important role in early lymphoid development.

Somatic stem cells and the origin of cancer

“…BMI1 is a gene member of the Polycomb Group family that has been involved in cancer 72 . In mouse models, forced expression of BMI1 in lymphocytes provokes lymphoma 73 whereas BMI1 is amplified and over-expressed in human mantle cell lymphoma 74 specially in Ki67+ proliferating cells 75 . BMI1 deletion in mice causes defects in hematopoiesis, neurological development and body growth 76 .…”

The Bmi-1 oncoprotein interacts with dinG and MPh2: the role of RING finger domains

“…A role for bmi-1 in the development of some lymphomas has been strengthened by the ®ndings that transgenic mice that overexpress bmi-1 are predisposed to lymphomas and that bmi-1 is overexpressed in naturally occurring lymphomas in feline leukemia virus-infected domestic cats (Haupt et al, 1993;Levy et al, 1993;Alkema et al, 1997b). To date, aberrant expression of bmi-1 has not been reported in human malignancies; however, a close homolog of bmi-1, mel18, is expressed at high levels in human melanoma cell lines (Tagawa et al, 1990).…”

“…Deletion of the RING ®nger abolishes the ability of Bmi-1 to transform cultured ®broblasts (Cohen et al, 1996). Further, mutations in bmi-1 that a ect conserved residues within the RING ®nger block the gene's ability to induce lymphomas in transgenic mice (Alkema et al, 1997b). These mutations have little e ect on the induction of axial skeletal anomalies mediated by Bmi-1.…”

“…Based on the observations that the Bmi-1 RING ®nger is essential for neoplastic transformation (Cohen et al, 1996;Alkema et al, 1997b) and that it may mediate protein interactions, we employed a yeast twohybrid selection to identify proteins that interact with the RING ®nger-containing amino-terminal portion of Bmi-1. The murine dinG/RING1B gene was isolated as a Bmi-1 interacting partner.…”

Overexpression of Frat1 in transgenic mice leads to glomerulosclerosis and nephrotic syndrome, and provides direct evidence for the involvement of Frat1 in lymphoma progression

“…This promoter/enhancer combination has been shown to give high transgene expression in both the B and T cell lineage (van Lohuizen et al, 1989;Renauld et al, 1994;Alkema et al, 1997). The Em-pp-Frat1 transgene lacks the Frat1 3' untranslated region containing putative mRNA destabilizing motifs, and expression of Em-pp-Frat1 should result in the production of truncated Frat1 mRNA, analogous to the transcripts found in lymphomas with a provirally activated Frat1 allele.…”