Induction of differentiation of retinoic acid-resistant acute promyelocytic leukemia cells by the combination of all-trans retinoic acid and granulocyte colony-stimulating factor.

An acute promyelocytic leukemia (APL) cell line with natural resistance to all-trans retinoic acid (ATRA), UF-1, was induced to differentiate into mature granulocyte when treated with the combination of ATRA and granulocyte colony-stimulating factor (G-CSF), while neither of them alone was capable of inducing the differentiation effectively. Continuous presence of both agents was required for the maximal differentiation-inductive effect. Neither proliferation arrest nor induction of apoptosis preceded the differentiation. Differentiated phenotype was accompanied by growth arrest, however, not by increased apoptosis. It was assumed that cellular events at the downstream of the signaling pathways of ATRA and G-CSF cooperatively played pivotal roles in the differentiation-induction.