Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy

Abstract

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by a severe bleeding tendency, accumulation of abnormal promyelocytes in the bone marrow and a reciprocal t(15;17) chromosomal translocation that fuses the gene encoding the promyelocytic leukemia protein (PML) to that encoding retinoic acid receptor alpha (RARA) (de The & Chen, 2010). During the past 30 years two therapeutic drugs have been introduced into the clinic that have dramatically improved the treatment outcome of this disease (Wang & Chen, 2008). The first of these components was all-trans retinoic acid (ATRA), a vitamin A derivative that significantly increased clinical remission and improved the 5-years disease-free survival rates from below 40% to more than 80% (Huang et al., 1988). The second drug was arsenic trioxide (ATO), a component that was discovered to be remarkably effective in treating APL as a single agent (Sun et al., 1992). Today, most hospitals employ ATRA in combination with chemotherapy as frontline therapy, while ATO is being used for refractory or relapsed patients. Recent clinical studies have also revealed a positive synergistic effect between the two drugs, suggesting that future therapy of newly diagnosed patients may involve a combination of the two reagents (Estey et al., 2006; Hu et al., 2009; Shen et al., 2004; Wang et al., 2004). The success of using ATRA and ATO in APL therapy appears to be linked to the ability of these drugs to interact with the fusion oncoprotein PML/RARA, which is produced by the APL-associated t(15;17) translocation, and that causes the disease. ATRA contacts a ligand binding domain present within the RARA moiety of this chimeric protein and promotes differentiation of APL cells along the granulocyte linage (Huang et al., 1988). ATO, on the other hand, has recently been shown to bind one or more cysteine rich motifs within the PML protein (Jeanne et al., 2010; Zhang et al., 2010) and contributes to the cure of APL through a mechanism that involves eradication of leukemic-initiating cells (LICs) (Nasr et al., 2008; Ito et al., 2008; Zheng et al., 2007). Due to the success of using ATRA and ATO in the clinic, and because of the ability of these drugs to promote clinical remission through a direct contact with PML/RARA, APL has become one of the most attractive model diseases for the development of targeted cancer therapy. The APL cure offers a proof of principle that a cancer can be cured through targeted inactivation of an oncoprotein, and it provides a rationale for the development of novel therapeutic strategies that target fusion oncoproteins produced by chromosomal translocations. In this chapter we will summarize the current knowledge of the biological