Differentiation Therapy for Myeloblastic Leukemia-Establishment of New Strategy

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The effects of all-trans retinoic acid (ATRA), either alone in combination with GM-CSF, on the induction of differentiation of a human myeloblastic leukemia cell line, ML-1, were investigated. ATRA alone caused only slight induction of NBT-reducing activity even at a high concentration (10-7M), but when combined with GM-CSF, it led to remarkable increase in the induction NBT reducing activity. Synergistic effect of both agents was also observed on morphological changes, the inhibition of cell proliferation and granulocytic characteristics such as esterase activity and expression of surface antigens. When ATRA pr GM-CSF was used alone, neither parameter was changed substantially for long periods of up to 9 days. However, the combination of both agents induced remarkable morphological changes with segmented nuclei and also suppressed DNA-synthesizing activity. The hypophosphorylated form of pRB during this differentiation process was observed. The expression of cyclin D3 cdc25A was markedly down regulated during differentiation. In contrast, Cdk2, Cdk4, Cdk6 and cyclins (A, D2, E) showed almost the same level of expression of CKIs (p21,p27,p57,p15,p16,p18 and p19) that inhibit cdk activity did not change during differentiation. These data suggest that change to the hypophosphorylated form of pRB is attributable to the repression of cyclin D3 and cdc25A genes.