Role of Abberant Proteolysis in the Pathogenesis of APL

Abstract

Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is caused by PML-RARN1, a fusion protein resulting from chromosomal translocation involving the promyelocytic leukemia (PML) and the retinoic acid receptor N1 (RARN1) genes. PML-RARN1 promotes misfolding of nuclear hormone receptor corepressor (N-CoR) and that accumulation of misfolded N-CoR in the ER induces endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). Although accumulation of misfolded proteins is known to trigger UPR-induced cytotoxic cell death in several neurodegenerative disorders, APL cells are notably resistant to UPR-induced apoptosis. This project was initiated with the goals to investigate how N-CoR misfolding supports the survival and growth of APL cells, and to screen potential therapeutic agents that could induce growth arrest through targeting the misfolded N-CoR-induced survival pathways in APL.