Investigating human leukemogenesis: from cell lines to in vivo models of human leukemia.
The hematopoietic system produces appropriate levels of blood cells over an individual's lifetime through a careful balance of differentiation, proliferation and self-renewal. The acquisition of genetic and epigenetic alterations leads to deregulation of these processes and the development of acute leukemias. A prerequisite to targeted therapies directed against these malignancies is a thorough understanding of the processes that subvert the normal developmental program of the hematopoietic system. This involves identifying the molecular lesions responsible for malignant transformation, their mechanisms of action and the cell type(s) in which they occur. Over the last 3 decades, significant progress has been made through the identification of recurrent genetic alterations and translocations in leukemic blast populations, and their subsequent functional characterization in cell lines and/or mouse models. Recently, primary human hematopoietic cells have emerged as a complementary means to characterize leukemic oncogenes. This approach enables the process of leukemogenesis to be precisely modeled in the appropriate cellular context: from primary human hematopoietic cells to leukemic stem cells capable of initiating disease in vivo. Here we review the model systems used to study leukemogenesis, and focus particularly on recent advances provided by in vitro and in vivo studies with primary human hematopoietic cells.
Kennedy
J A
JA
Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, Canada.
Barabé
F
F
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*