IN THE LATE 1980s and early 1990s, the elucidation of the molecular basis of acute promyelocytic leukemia (APL) emerged as a paradigm for the connection between the bench and bedside. At that time, it became apparent that APL was, among the forms of acute myeloid leukemia, uniquely sensitive to all-trans retinoic acid (ATRA) 1, 2 and clinical trials indicated that ATRA induced complete remissions by differentiation and eventual elimination of the malignant clone (reviewed previously3-8). In 1991, it was discovered that the consistent chromosomal translocation of APL, t (15: 17), 9 fused the retinoic acid receptor (RAR) gene to the promyelocytic leukemia (PML) gene on chromosome 15, yielding the fusion protein PMLRAR. 10-15 These data suggested that disruption of RAR function was the major cause of APL. According to this line of reasoning, retinoic acid in pharmacological doses could then overcome this pathology, leading to in vivo differentiation and clinical remission. Although this hypothesis is essentially correct, 7 years of intense investigation of the APL model have begun to uncover a more complicated picture. APL is now associated with four different gene rearrangements, fusing RAR to the PML, promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), or nuclear matrix associated (NuMA) genes (Fig 1), leading to the formation of reciprocal fusion proteins (N-RAR and RAR-N). This again highlights the importance of retinoid metabolism, but also suggests that partner genes with RAR could also play important roles. In this review, we will deconstruct the APL problem by evaluating the role of RAR in normal and neoplastic myeloid development. We will examine each of the genes fused to the RAR in APL, searching for similarities and differences among the four partner proteins that may explain the distinct clinical outcome some patients with variant forms of APL. Finally, we will reconstruct the disease of APL and examine the leukemogenic functions of the RAR fusion proteins in cell culture models, animal models, and patients. We will also examine how the recent explosion of knowledge in APL has led to the development of new therapeutic agents such as arsenic trioxide16, 17 and sodium butyrate.

THE RETINOIC ACID RECEPTOR Retinoids may be key for myeloid differentiation. Vitamin A-deficient mice and humans were noted to have defects in hematopoiesis18, 19 and retinoids can preferentially stimulate granulopoiesis. 20, 21 In the early 1980s, it was noted that retinoic acid (ATRA) could induce differentiation of myeloid cell lines such as HL6022 and of primary cells from patients with APL. 23 The cloning of the RARs and other members of the nuclear receptor superfamily24-26 allowed for further detailed studies into the mechanism of action of ATRA. Among the genes encoding RARs (reviewed previously24-26), RAR is identified with myeloid development. 27-29