Oncogenesis by Abl Family Oncoproteins

The abl oncogene plays a central role in several types of human leukemias. Our laboratory seeks to understand the molecular mechansims by which altered expression of Abl family proteins induces disease and is working to develop and test new therapeutic modalities to combat these diseases. Two major approaches are being taken: (1) the study of the c- abl gene products, their functional roles, localization, and regulation; (2) expression of oncogenic abl genes in the hematopoietic system of mice.

c-Abl is a non-receptor protein-tyrosine kinase localized to the nucleus and cytoskeleton whose normal function is unknown. Nuclear and cytoskeletal localization of Abl is controlled by the regulation of three nuclear localization signals and an actin-binding domain in the C-terminus of the protein. In the nucleus, Abl binds to DNA and induces a p53- and pRb-dependent cell cycle block, suggesting a physiological role for Abl in negative control of cell growth. The kinase activity of c-Abl is tightly regulated through the Abl src homology 3 (SH3) domain. Enzymological studies of purified c-Abl suggest SH3 functions in part to inhibit Abl intramolecularly, while Abl kinase activity is further suppressed in vivo through binding of an inhibitor. We recently identified Pag/Prdx1, a member of the peroxiredoxin family of antioxidant proteins, as a physiological inhibitor of c-Abl and demonstrated that its inhibition of Abl is regulated by free radicals, suggesting a role for c-Abl in the cellular response to oxidative stress. Mice lacking Prdx1 exhibit shortened survival due to development of hemolytic anemia and multiple malignant cancers, demonstrating one of the first experimental links between free radicals, aging, and cancer. Our current work focuses on elucidating the functional roles of Abl and Prdx1 and the regulatory mechanisms involved, employing both a direct biochemical approach with purified proteins and genetic approaches with mutants and knockout mice and cells.

Bcr-Abl is an oncogenic form of Abl generated by the Philadelphia chromosome translocation in the human malignancy chronic myeloid leukemia (CML). We have developed methods for the expression of Bcr-Abl in bone marrow of mice by ex vivo retroviral gene transfer and bone marrow transplantation, and shown that expression of Bcr-Abl induces a CML-like leukemia in mice. We are utilizing this system and other technology such as transgenic mice to develop a molecular understanding of the leukemias induced by these genes. Current goals include identification of bone marrow target cells for transformation by Bcr-Abl, analysis of the leukemogenic activity of different forms and mutants of Bcr-Abl, and identification of signaling pathways critical for leukemogenesis through use of mutant donor and recipient mice.