Cell Differentiation and Programmed Cell Death: A New Approach to Leukemia Therapy

Abstract

The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hematopoietic cell lineages and the molecular basis of normal and abnormal cell development in blood forming tissues. These regulators include cytokines now called colony stimulating factors and interleukins. Different cytokines can induce cell viability, multiplication and differentiation, and hematopoiesis is controlled by a network of cytokine interactions. Cytokines induce viability by inhibiting programmed cell death (apoptosis) including inhibition of apoptosis in leukemic cells treated with cytotoxic chemotherapy and irradiation therapy. Apoptosis and development of hematopoietic cells are also controlled by different genes including the tumor suppressor gene wild-type p53 and the oncogenes mutant p53, deregulated c-myc and bcl-2. Identification of the molecular controls of normal cell viability, growth and differentiation have made it possible to identify changes in the developmental program that result in leukemia. When normal cells have been changed into leukemic cells, the malignant phenotype can again be suppressed by inducing differentiation and apoptosis. Results on the suppression of malignancy in myeloid leukemia have shown that suppression of malignancy does not have to restore all the normal controls, and that genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation and apoptosis. The results provide a new approach to therapy.