Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs

Over the past decade, there has been an exponential increase in our knowled ge of how cytokines regulate signal transduction, cell cycle progression, d ifferentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identifi ed by clonogenic assays and purified by biochemical techniques. This soon l ed to the molecular cloning of the genes encoding the cytokines and their c ognate receptors. Determining the structure and regulation of these genes i n normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of m odified cytokines which are able to stimulate multiple receptors and be mor e effective in stimulating the repopulation of hematopoietic cells after my elosuppressive chemotherapy. The mechanisms by which cytokines transduce th eir regulatory signals have been evaluated by identifying the involvement o f specific protein kinase cascades and their downstream transcription facto r targets. The effects of cytokines on cell cycle regulatory molecules, whi ch either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptoti c proteins, which mediate survival vs death, are being elucidated. Identifi cation and characterization of these complex, interconnected pathways has e xpanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to ta rget key intermediates in these pathways and effectively treat patients wit h leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate recept or, are expressed and the mechanisms by which they transmit their growth re gulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transf ormed hematopoietic cells are discussed. Finally, anti-neoplastic drugs tha t target crucial constituents in these pathways are evaluated.