Pharmacological doses of ATRA predominantly drive differentiation of leukemic blasts, but are unable to efficiently eliminate LICs that can drive disease relapse (right). promyelocytic leukemia (APL) was first described as an independent condition in 1957 (Hillestad, 1957) and presents clinically Pirmenol hydrochloride as a replacement of normal hematopoiesis in the bone marrow by an accumulation of promyelocytes, which are precursors of granulocytes. It is an aggressive disease associated with a high frequency of bleeding and thrombosis, and is rapidly fatal if not properly treated and managed. (Choudhry and DeLoughery, 2012; Kwaan and Huyck, 2010). The vast majority of APL cases are characterized by the fusion of the N-terminus of the promyelocytic leukemia protein (PML) to the C terminus of Pirmenol hydrochloride the retinoic acid receptor-a (RARa) transcription factor (Borrow et al., 1990; Chomienne et al., 1990; de Th et al., 1990, 1991; Longo et al., 1990; Alcalay et al., 1991; Kakizuka et al., 1991; Pandolfi et al., 1991) as a result of a balanced chromosomal translocation, t(15;17)(q22;q12; Rowley et al., 1977). In variant forms of APL, RARa is fused to one of its alternative N-terminal partners including promyelocytic leukemia zinc finger (PLZF), nucleophosmin 1 (NPM1), nuclear mitotic apparatus (NUMA), signal transducer and activator of transcription 5B (STAT5b), protein kinase, IL18RAP cAMP-dependent, regulatory, type I, (PRKAR1A), FIP1-like 1 (FIP1L1), BCL6 co-repressor (BCOR) and oligonucleotide/oligosaccharide-binding fold containing 2A (OBFC2A; Zelent et al., 2001; Redner, 2002; Catalano et al., 2007; Kondo et al., 2008; Yamamoto et al., 2010; Won et al., 2013). Although rare, these Pirmenol hydrochloride variant forms of APL have been very informative in elucidating the molecular mechanisms underlying the biological functions of the resulting fusion oncoproteins, especially PLZF-RARa, the most common and studied variant. This review is focused primarily on PML-RARa APL, and unless clearly stated, does not apply to the other translocations. The molecular mechanism of transformation in APL has been extensively reviewed in numerous recent publications (Wang and Chen, 2008; de Th and Chen, 2010; de Th et al., 2012). In brief, RARa is a nuclear receptor that in the absence of its ligand retinoic acid (RA) represses the transcription of target genes by recruiting co-repressors and histone deacetylases. Physiological levels of RA Pirmenol hydrochloride convert RARa from a transcriptional repressor into a potent activator, driving expression of genes involved in myeloid differentiation. In contrast, PML-RARa remains an ineffectual transcriptional activator even in the presence of physiological RA levels. Additionally, by forming heterodimers with PML, PML-RARa antagonizes the formation of nuclear bodies (NBs), which are macromolecular structures that regulate the P53 pathway among many other activities. Thus, after a classical model of leukemogenesis, PML-RARa is thought to simultaneously contribute two oncogenic hits in one: the block of differentiation and the aberrant self-renewal of APL cells. A variety of pharmacological interventions have proven effective against the disease. In particular, APL cells have been shown to be exquisitely sensitive to all-trans-RA (ATRA) and arsenic trioxide (ATO), which together with advances in chemotherapy (CT) and improvements in transfusion support therapy, have transformed the therapeutic landscape and converted a highly fatal disease into a highly curable one (Wang and Chen, 2008). Although widely regarded as targeted therapies because of their selective effects on the PML-RARa fusion protein, both ATRA and ATO are naturally derived compounds. Their clinical application preceded the detailed scientific understanding of their mechanisms of action and drove subsequent efforts to determine the molecular and biological processes underlying their tremendous efficacy. In this review, we will critically summarize current knowledge in the field of APL therapeutics, with particular emphasis on two interconnected questions that remain vigorously debated: (1) what is the contribution of reversing the block of differentiation of APL blasts vis-a-vis the elimination of the leukemia-initiating cell (LIC) pool on the effective treatment of the disease, and (2) is the reversal of transcriptional repression or the proteolytic degradation of PML-RARa more important? THE ATRA REVOLUTION ATRA induces remission without cure ATRA was first shown to be capable of inducing differentiation in the cell line HL-60 and in primary APL specimens in vitro in 1981 (Breitman et al., 1981). The first description of ATRA as an APL therapy was subsequently published by a group from the Shanghai Institute of Hematology in 1988 (Huang et al., 1988). The study documented the use of ATRA as a single agent in induction therapy for 24 patients, 16 of whom were receiving.