Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia.
نویسندگان
چکیده
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 a (RARa) gene to the promyelocytic leukemia (PML) gene on chromosome 15, yielding the fusion protein PMLRARa.10-15 These data suggested that disruption of RARa 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 RARa 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-RARa and RARa-N). This again highlights the importance of retinoid metabolism, but also suggests that partner genes with RARa could also play important roles. In this review, we will deconstruct the APL problem by evaluating the role of RARa in normal and neoplastic myeloid development. We will examine each of the genes fused to the RARa 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 RARa 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.
منابع مشابه
Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha.
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARalpha and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RARalpha and NPM-RARalpha. PLZF-RARalpha transgenic animals developed chronic myeloid leukemia-like phenotypes at an e...
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عنوان ژورنال:
- Blood
دوره 93 10 شماره
صفحات -
تاریخ انتشار 1999