Tumor cells are characterized by their arrest at stages of incomplete maturation with retention of their capacity for sustained growth. Therefore, approaches leading to the initiation of their differentiation hold promise for use in cancer therapy. To identify such approaches. studies are proposed dealing with the mechanisms by which growth- and differentiation signals control the proliferation and maturation of ML-1 human myeloblastic leukemia cells. Our recent findings have shown that two stages -competence and progression- are involved in the differentiation process, the former stage being controlled by the cytokines TNF-alpha and TGF-beta, the latter by transferrin, isolated from leukocyte-conditioned medium and identified by sequencing. The mechanisms by which these two phases are activated and the relationship they bear to the parallel phases activated by growth factors is to be studied by 1) examining the effects differentiation-specific competence factors exert on the expression and the extent of phosphorylation of the receptor for the differentiation-progression factor transferrin; 2) determining the effect the differentiation-specific competence and progression signals exert on the expression of diverse proto-oncogenes generally considered to be involved in the control of cell proliferation; 3) exploring the ability of differentiation-determining competence and progression factors to bring about the therapeutic reduction of ML-1 leukemic cell populations when applied alone or in combination with DNA-specific drugs, which render the cells sensitive to differentiation; 4) measuring the binding characteristics of the ML-1 growth-stimulating and differentiation-inducing competence factors; 5) assaying the reciprocal, concentration-dependent effects ML-1 growth- and differentiation factors exert on each others' signals and 6) determining the nature of the phospholipases targeted, the phosphoinositide metabolites generated and the PKC subspecies activated by growth- as compared to differentiation-inducing factors.
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