Acute leukemias result when the regulation of the normal hematopoietic process goes awry at the stem cell or progenitor levels. Benzene (BZ) is an aromatic hydrocarbon in widespread use as an industrial chemical, and is known to play a causative role in the development of certain cases of acute myeloid leukemia (AML). The leukemogenic properties of BZ and its metabolites are thought to occur via effects on normal hematopoietic precursors, but the precise cellular events responsible for benzene-induced leukemogenesis remain unknown. One group of proteins that are potential candidates for such causative effects is the protein kinase C (PKC) family of serine-threonine kinases. These kinases are activated by a wide range of stimuli, including BZ and oxidative stress, and exhibit context-dependent and isoform-specific effects on cell proliferation and differentiation. This proposal will examine the expression and functional roles of the PKC family of proteins in normal hematopoiesis and will determine whether abnormalities in the expression of PKC proteins contributes to the development of AML, including AML related to benzene exposure.
Specific aim A is to determine the role of the PKC family in normal hematopoiesis. Studies will be performed to define the expression of different PKC-isoforms during early and late stages of normal erythropoiesis and myelopoiesis, and to examine the effects of disruption of their expression or inhibition of their kinase activities on hematopoietic progenitor cell growth and differentiation.
Specific aim B is to determine the role of the PKC family in AML. The patterns of expression of PKC members and their contribution to leukemogenesis will be investigated in primary leukemic progenitors from the bone marrows of patients with AML and will be correlated to prior exposure to benzene. Project relevance: Environmental exposures to benzene and other carcinogens can lead to the development of different forms of AML, thus understanding the mechanisms by which such carcinogens promote the onset of leukemic phenotypes is an essential step towards the development of novel therapies and the prevention of such leukemias. Among the known cellular targets of benzene is the PKC family of proteins, but very little is known about the expression and pathogenetic role of these kinases in benzene-related cases of acute leukemia. This proposal is a comprehensive approach to examine the function of PKC isotypes in normal hematopoietic progenitors and to identify abnormalities in their expression in AML, thereby providing valuable information on the mechanisms by which environmental carcinogens promote leukemogenesis and leading to the identification of novel targets for acute leukemia treatment. ? ? ?
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