Inhibition of granulocytic differentiation of acute promyelocytic leukemia cells in primary culture by transforming growth factor-β

Abstract

We investigated the effect of transforming growth factor- β 1 (TGFβ) 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 TGFβ on growth and differentiation of APL cells. DNA synthesis, determined by 3H-thymidine uptake, was inhibited in the presence and absence of granulocyte colony-stimulating factor (G-CSF) in a dose-dependent manner by TGFβ in APL cells obtained from three of the four cases. TGFβ 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 TGFβ 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 TGFβ is a negative regulator of the proliferation and differentiation of APL cells. The significance of TGFβ as an endogenous regulator in differentiation therapy with RA of APL patients is discussed.