The peripheral cannabinoid receptor Cb2 in leukemia

Acute myeloid leukemia (AML) is a blood cell disorder characterized by an accumulation of immature blasts in bone marrow and blood. Human AML is frequently characterized by non-random chromosome translocations resulting in the generation of specific transforming fusion genes and fusion proteins, of which a significant number has been cloned, e.g. AML1-ETO fusion gene in AML with a t(8;21) translocation or PML-RAR in cases with translocation t(15;17). However, in approximately 40 - 50% of AML cases no chromosomal abnormalities are evident, indicating that other more subtle mutations are responsible for the leukemic transformation of myeloid precursor cells. Moreover, AML, like other cancers, is a multigenic disease resulting from an accumulation of multiple genetic aberrations. Thus even in cases with well-characterized translocations, additional genetic defects have likely contributed to the development of AML. The identification and functional analysis of novel disease genes in AML is a major goal of our research group. One approach utilized to identify novel disease genes in leukemia is retroviral insertional mutagenesis. Mice injected with murine leukemia viruses (MuLVs) develop leukemia following proviral insertion into or near potential disease genes. Viral insertions found in a particular locus in independent tumors are called common virus integration sites, cVIS, and mark the locations of potential proto-oncogenes or tumor suppressor genes. The mouse strain and the type of retrovirus used will determine the kind of leukemia that will develop. We used NIH/Swiss mice injected with Cas-Br-M MuLV which develop frequently myeloid leukemias. Using this combination, we previously identified the cVIS Evi11 and demonstrated that the gene encoding the peripheral cannabinoid receptor Cb2 is the likely target gene. Cb2 encodes a seven transmembrane receptor that belongs to the G proteincoupled receptor (GPCR) family and is predominantly present on B lymphocytes. The main objective of the work presented in this thesis is to determine whether Cb2 is indeed a proto-oncogene and, if so, by which mechanism it may transform hematopoietic precursor cells.