Fenretinide (4-HPR) is a synthetic retinoid with cancer chemopreventative potential and clinically manageable side effects, compared to the prototype retinoid, all-trans retinoic acid (RA). 4-HPR has been shown to modulate cell proliferation and induce apoptosis in a variety of human tumor cell types, but its effects on B-cell non-Hodgkin's lymphomas (NHL-B) have not been explored. Treatment of Burkitt's lymphoma Mutu I cells with 3 mu M 4-HPR. is accompanied by growth arrest, induction of apoptosis, and restricted progression of the cell cycle at the G(1)/S checkpoint. We also observed that 4-HPR elicited a reduced expression of bcl-6 in these cells, which supports the proposed role of bcl-6 as an anti-apoptotic gene. While 4-HPR treatment had no effect on total Rb gene expression, it significantly reduced the state of hyperphosphorylation of Rb, resulting in the predominant existence of Rb in the underphosphorylated state.