Role of Nuclear Receptor Corepressors in Leukemogenesis

Abstract

In the past two decades important steps have been taken towards the understanding of the molecular pathogeneses that underlie many malignant diseases. Studies in cancer genetics have identified loci which play central roles in the regulation of cell proliferation and differentiation and whose mutations are associated with tumorigenesis. Functional characterizations of these loci often demonstrated that they encode factors, which are directly involved in transcriptional regulation of gene expression. The last two decades have also seen some remarkable advances in the treatment of cancer, particularly hematopoietic malignancies, where acute promyelocytic leukemia (APL) has led the way both in treatment innovation and in the understanding of the molecular events underlying the disease process. The demonstration that APL could respond to differentiation therapy with all-transretinoic acid (ATRA) as a sole therapeutic agent has made this relatively rare hematopoietic malignancy a model disease. Interest in APL was further enhanced by the discovery that the retinoic acid receptor-α (RARα) locus, a member of the nuclear receptor (NR) superfamily, was reciprocally translocated to a gene of unknown function called PML (for Promyelocytic Leukemia) leading to expression of PML-RARa and RARa-PML fusion proteins. This article will review the current understanding of the role that the NR corepressors play in the molecular pathogenesis of APL and address recent data directly implicating these molecules in processes associated with the development of more common myeloid and lymphoid malignancies.