INHIBITION OF GRANULOCYTIC DIFFERENTIATION OF ACUTE PROMYELOCYTIC LEUKEMIA-CELLS IN PRIMARY CULTURE BY TRANSFORMING GROWTH-FACTOR-BETA

We investigated the effect of transforming growth factor-beta1 (TGFbeta3) on the proliferation and differentiation of cultured acute promyelocytic leukemia (APL) cells with the chromosomal t(15;17) translocation obtained from four patients to determine the role of TGFbeta on growth and differentiation of APL cells. DNA synthesis, determined by H-3-thymidine uptake, was inhibited in the presence and absence of granulocyte colony-stimulating factor (G-CSF) in a dose-dependent manner by TGFbeta in APL cells obtained from three of the four cases. TGFbeta and G-CSF did not significantly affect the differentiation of APL cells, but all-trans retinoic acid (RA) induced morphological and functional differentiation in all APL cells tested. G-CSF markedly enhanced RA-induced granulocytic differentiation in APL cells obtained from all four cases. In cells in which TGFbeta inhibited DNA synthesis, it also inhibited RA-induced granulocytic differentiation of APL cells and, to a greater degree, granulocytic differentiation induced by RA plus G-CSF. These results suggest that TGFbeta is a negative regulator of the proliferation and differentiation of APL cells. The significance of TGFbeta as an endogenous regulator in differentiation therapy with RA of APL patients is discussed.