Why is differentiation induction an effective therapy for hematologic malignancies?
In many acute leukemias and some lymphomas, aberrant differentiation is a major feature of the malignant phenotype that often results from a single genetic alteration and hence provides a site-specific target for therapy (Look, 1997). The oncogenic event frequently leads to the generation of a fusion gene that facilitates proliferation by inhibiting a tumor suppressor gene and also disrupts signaling pathways required for differentiation (Melnick and Licht, 1999). In many cell lines and primary cultures derived from hematologic malignancies the malignant phenotype can be abrogated by inducing differentiation, terminal cell division or programmed cell death (apoptosis) by a variety of agents (Table 1) (Ferrari and Waxman, 1994). Interestingly, many of these agents at low concentrations induce differentiation and terminal cell division with minimal apoptosis while at higher concentration, usually by an alternative pathway, induce apoptosis with minimal evidence of differentiation (Finnin
