The in vitro effects of all- trans-retinoic acid and hematopoietic growth factors on the clonal growth and self-renewal of blast stem cells in acute promyelocytic leukemia

Abstract

All- trans-retinoic acid (ATRA) has been used as a potent therapeutic agent to induce differentiation of acute promyelocytic leukemia (APL) cells, and granulocyte colony-stimulating factor (G-CSF) has been reported to enhance this effect of ATRA in vitro. We investigated the effects of ATRA and three myeloid growth factors, including G-CSF, on the growth of the leukemic stem cells of 10 APL patients. G-CSF was the most powerful stimulator of leukemic colony formation in five out of 10 patients, but was neither the major stimulant of self-renewal of the blast stem cells nor an inducer of maturation. In contrast, ATRA was highly effective in inducing morphological maturation of leukemic promyelocytes, but variable results were obtained in regard to its effects on the growth of blast stem cells: ATRA suppressed both clonal growth and self-renewal in some patients, but was inactive or even had stimulating effects in the other patients. Similar variable effects were observed with the combination of ATRA and G-CSF. These findings indicate that the differentiation-inducing effect of ATRA is not always associated with growth inhibition of leukemic stem cells in vitro and justify the use of chemotherapy in conjunction with ATRA in the treatment of APL.