Cytokine control of developmental programs in normal hematopoiesis and leukemia.

The establishment of a system for in vitro clonal development of hematopoietic cells made it possible to discover the cytokines that regulate hematopoiesis. These cytokines include colony stimulating factors and others, which interact in a network, and there is a cytokine cascade which couples growth and differentiation. A network allows considerable flexibility and a ready amplification of response to a particular stimulus. A network may also be necessary to stabilize the whole system. Cells called hematopoietic stem cells (HSC) can repopulate all hematopoietic lineages in lethally irradiated hosts, and under appropriate conditions give rise to neuronal, muscle, and epithelial cells. Granulocyte colony stimulating factor induces migration of both HSC and in vitro colony forming cells from the bone marrow to peripheral blood. Granulocyte colony stimulating factor is also used clinically to repair irradiation and chemotherapy associated suppression of normal hematopoiesis in cancer patients, and to stimulate normal granulocyte development in patients with infantile congenital agranulocytosis. It is suggested that there may also be appropriate conditions under which in vitro colony forming cells have a wider differentiation potential similar to that shown by HSC. An essential part of the developmental program is cytokine suppression of apoptosis by changing the balance in expression of apoptosis inducing and suppressing genes. Decreasing the level of cytokines that suppress therapeutic induction of apoptosis in malignant cells can improve cancer therapy. Cytokines and some other compounds can reprogram abnormal developmental programs in leukemia, so that the leukemic cells differentiate to mature non dividing cells, and this can also be used for therapy. There is considerable plasticity in the developmental programs of normal and malignant cells.