Accumulation of gamma-globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine

Human leukaemic K562 cells can be induced in vitro to erythroid differentia tion by a variety of chemical compounds, including haemin, butyric acid, 5- azacytidine, cytosine arabinoside, mithramycin and chromomycin, cisplatin a nd cisplatin analogues. Differentiation of K562 cells is associated with an increase of expression of embryofetal globin genes, such as the zeta-, eps ilon- and gamma -globin genes. The K562 cell line has been proposed as a ve ry useful in vitro model system to determine the therapeutic potential of n ew differentiating compounds as well as to study the molecular mechanism(s) regulating changes in the expression of embryonic and fetal human globin g enes. Inducers of erythroid differentiation stimulating gamma -globin synth esis could be considered for possible use in the therapy of haematological diseases associated with a failure in the expression of normal beta -globin genes, We have analysed the effects of tallimustine and distamycin on cell growth and differentiation of K562 cells. The results demonstrated that ta llimustine is a potent inducer, while distamycin is a weak. inducer, of K56 2 cell erythroid differentiation. Erythroid differentiation was associated with an increase of accumulation of gamma -globin mRNA and of production of both haemoglobin (Hb) Gower 1 and Hb Portland. In addition, tallimustine-m ediated erythroid induction occurred in the presence of activation of the a poptotic pathway. The reasons for proposing tallimustine as an inducer of g amma -globin gene expression are strongly sustained by the finding that thi s compound stimulates fetal haemoglobin production in human erythroid precu rsor cells from normal subjects.