Expression of BCR-ABL in M1 myeloid leukemia cells induces differentiationwithout arresting proliferation

The mechanism leading to the expanding population of maturing myeloid cells which characterises chronic myeloid leukemia (CML) remains obscure. Becaus e of its ability to mimic the proliferative and cell survival functions of hematopoietic growth factors, me hypothesized that the oncogene activated i n CML, BCR-ABL, might also influence differentiation. To test this hypothes is, nle examined the effects of expressing BCR-ABL on the myeloid different iation of murine M1 leukemic cells, which cease dividing and differentiate into macrophages in the presence of the cytokines leukemia inhibitory facto r (LIF) or interleukin (IL)-6, We found that BCR-ABL induced macrophage dif ferentiation in M1 cells, accompanied by increased expression of macrophage cell surface markers and the acquisition of phagocytic ability. Interestin gly, clones of M1 cells which expressed BCR-ABL remained in cell cycle and were refractory to the growth inhibition and apoptosis induced by IL-6 or L IF in parental M1 cells. These cells also expressed inappropriately high le vels of c-MYC mRNA for their degree of differentiation, which may have been important in maintaining cellular proliferation. These data suggest that B CR-ABL can stimulate both differentiation and proliferation and that these characterisitics may contribute to the phenotype observed in CML.