Year: 2004
Type: dissertation
Abstract: Acute myeloid leukemia (AML) is a blood cell disorder characterized by an accumulation \nof immature blasts in bone marrow and blood. Human AML is frequently characterized by \nnon-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. \nAML1-ETO fusion gene in AML with a t(8;21) translocation or PML-RAR in cases with \ntranslocation t(15;17). However, in approximately 40 - 50% of AML cases no chromosomal \nabnormalities are evident, indicating that other more subtle mutations are responsible for \nthe leukemic transformation of myeloid precursor cells. Moreover, AML, like other cancers, \nis a multigenic disease resulting from an accumulation of multiple genetic aberrations. \nThus even in cases with well-characterized translocations, additional genetic defects have \nlikely contributed to the development of AML. The identification and functional analysis of \nnovel disease genes in AML is a major goal of our research group. \nOne approach utilized to identify novel disease genes in leukemia is retroviral insertional \nmutagenesis. Mice injected with murine leukemia viruses (MuLVs) develop leukemia \nfollowing proviral insertion into or near potential disease genes. Viral insertions found in a \nparticular locus in independent tumors are called common virus integration sites, cVIS, \nand mark the locations of potential proto-oncogenes or tumor suppressor genes. The \nmouse strain and the type of retrovirus used will determine the kind of leukemia that will \ndevelop. We used NIH/Swiss mice injected with Cas-Br-M MuLV which develop frequently \nmyeloid leukemias. Using this combination, we previously identified the cVIS Evi11 and \ndemonstrated that the gene encoding the peripheral cannabinoid receptor Cb2 is the likely \ntarget gene. Cb2 encodes a seven transmembrane receptor that belongs to the G proteincoupled receptor (GPCR) family and is predominantly present on B lymphocytes. The \nmain objective of the work presented in this thesis is to determine whether Cb2 is indeed \na proto-oncogene and, if so, by which mechanism it may transform hematopoietic precursor cells.
Author: Meritxell Alberich-Jordà
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2111878078