Lysosomes and Trivalent Arsenic Treatment in Acute Promyelocytic Leukemia

Cells from patients with t(15;17) acute promyelocytic leukemia (APL) express a fusion protein between the promyelocytic leuke-mia protein and retinoic acid receptor α (PML/RAR α) that blocks differentiation of promyelocytes and leads to accumulation of leukemic promyelocytes ( 1). Most patients with APL respond to treatment with all- trans-retinoic acid by degrading the PML/RAR α protein through proteasome-dependent ( 2, 3) as well as caspase-dependent ( 2, 4) degradation pathways; this degradation triggers ter-minal differentiation of APL cells. However, all- trans-retinoic acid treatment causes toxic effects that are often clinically dose limiting ( 5), and APL can develop resistance to all- trans-retinoic acid ( 1, 5). Therefore, an alternative nonretinoid therapy for APL was needed. For centuries, arsenic has been used as a therapeutic agent to treat, e.g., ulcer, plague, and malaria, as reviewed ( 6). Resurgent interest in arsenic-based cancer therapy was generated by reports ( 7, 8) that arsenic induced clinical remission in APL patients, includ-ing patients with APL resistant to all- trans-retinoic acid. In these studies, patients were treated with arsenic trioxide (As 2 O 3), a triva-lent arsenic (arsenite) that is the biologically and therapeuticall