The results have shown that differentiation-competent clones (called D+ clones) of mouse leukemic cells induced to differentiate with a cytokine such as IL-6 to mature nondividing cells by the normal sequence of gene expression (15, 26, 53, 54) were no longer malignant when injected into mice (55). In addition to DI clones that can be induced to differentiate by IL-6 and can also be induced to partially differentiate with G-CSF, there are DI clones from another myeloid leukemia that can be induced to differentiate with GM-CSF or IL-3 but not with IL-6 or G-CSF (26-29). In clones that respond to these CSFs, the growth inducers presumably induce production of an appropriate differentiation inducer. DI leukemic cells that respond to IL-6 can also be induced to differentiate' by IL-1a and IL-113, and this is mediated by the endogenous production of IL-6 (27). The DI myeloid leukemic cells have an abnormal chromosome composition (56, 57). Suppression of malignancy in these cells was not associated with chromosome changes and the differentiating leukemic cells did not regain the normal diploid chromosome complement. The stopping of cell multiplication by inducing differentiation to mature cells thus bypassed genetic changes that produced the malignant phenotype, such as a loss of requirement for a normal cytokine for cell viability and multiplication, and a block in the ability of a multiplication inducing cytokine to induce the production of a differentiation inducing cytokine (reviewed in refs. 25-27 and 58).