title: Interplay of protein misfolding pathway and unfolded-protein response in acute promyelocytic leukemia.
abstract: Protein misfolding has traditionally been linked to the pathogenesis of various neurodegenerative diseases. However, emerging evidence from various laboratories, including ours, suggests that protein misfolding may also play a fundamental role in some malignancies, particularly those caused by fusion oncoprotein generated from chromosomal translocation. Promyelocytic leukemia (PML) fused to the retinoic acid receptor (RAR) is a fusion oncoprotein linked to the transformation of acute promyelocytic leukemia (APL), and is not only a misfolded protein itself, but also promotes misfolding of nuclear receptor corepressor (N-CoR) protein, a corepressor essential for the growth-suppressive function of several tumor-suppressor proteins. PML-RAR promotes misfolding of N-CoR by inducing aberrant post-translational modification, which destabilizes its core and promotes instability. Misfolded N-CoR, thus, contributes to differentiation arrest and survival of APL cells through loss-of-function and aberrant gain-of-function properties. Therapeutic restoration of N-CoR conformation and function with conformation-modifying agents not only releases this differentiation arrest but also sensitizes APL cells to programmed cell death. These findings illustrate the potential of the misfolded N-CoR protein as a conformation-based drugable molecular target for APL, and highlights the promise of various conformation-modifying agents as novel therapeutics for APL. Protein conformational rearrangement, resulting from an inherited or acquired genetic alteration, could be a common pathological phenomenon contributing to transformation in different types of leukemias and solid tumors and, therefore, could serve as a common ground for designing a unifying diagnostic as well as therapeutic approach for a widely diverse disease such as cancer. To that end, APL could serve as a model for the development of a novel conformation-based therapeutic approach for other malignant diseases.
authors.affiliation: Cancer Science Institute of Singapore (CSI) and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Center for Life Sciences, Block MD11, Singapore. csimmk@nus.edu.sg
authors.forename: Matiullah
authors.initials: M
authors.lastname: Khan
mesh_terms: D000818:Animals; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry*; D017510:Protein Folding
chemical_list: D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein