title: The role of the proteasome in AML.
abstract: Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML. Pre-clinical studies have demonstrated that proteasome inhibition disrupts proliferative cell signaling pathways, exhibits cytotoxic synergism with other chemotherapeutics and induces autophagy of cancer-related proteins. Meanwhile, clinical trials incorporating bortezomib into combination chemotherapy regimens have reported a range of responses in AML patients, with complete remission rates >80% in some cases. Taken together, this preclinical and clinical evidence suggests that inhibition of the proteasome may be efficacious in this disease. In an effort to focus further investigation into this area, these recent studies and their findings are reviewed here.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Csizmar
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: D-H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Sachs
mesh_terms: D001343:Autophagy / Q000187:drug effects; D000069286:Bortezomib / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; D000069286:Bortezomib; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex