The peripheral cannabinoid receptor, Cb2, in retrovirally-induced leukemic transformation and normal hematopoiesis

Following retroviral insertional mutagenesis we recently identified the gene encoding the peripheral cannabinoid receptor (Cb2) near a common virus integration site (VIS), Evi11. In 13 out of 105 Cas-Br-M murine leukemia virus (MuLV) induced leukemias retroviral integrations occured either in the 5' or 3' part of the Cb2 gene. The Cb2 receptor protein is 44% homologous to the central cannabinoid receptor Cb1, which belongs to the superfamily of seven transmembrane (7TM) receptors. Cb1 is mainly expressed in brain, whereas Cb2 encodes the hematopoietic form. Besides the natural cannabinoids, delta9-tetrahydrocannabinol (delta9-THC) and cannabinol, and the many synthetic agonists that have been generated, e.g CP55,940 or WIN55,212-2, several endogenous ligands have recently been identified. These include the arachidonic acid derivatives anandamide and 2-arachidonylglycerol as well as the fatty acid palmitoylethanolamide. Although in the past many studies described growth inhibitory effects of cannabinoid agonists on the in vitro proliferation of hematopoietic cells, recent studies demonstrated that activation of Cb2 may have growth stimulatory effects on blood precursor cells. We demonstrated that many murine hematopoietic growth factor (HGF) dependent cell lines also require the presence of anandamide for optimal growth in serum free culture. Thus, the Cb2 receptor may be an important regulator of normal hematopoietic growth and development. These results strengthen our finding that Cb2 is a proto-oncogene and may implicate a growth advantage for leukemia cells that aberrantly express Cb2. Here we briefly review the mechanisms and application of retroviral insertional mutagenesis in leukemic transformation in mice and discuss the role of the peripheral cannabinoid receptor in leukemia development and normal hematopoiesis.