Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

• Published in: Leukemia Vol. 27; no. 12; pp. 2357 - 2365
• Main Authors: Schmidt, J, Braggio, E, Kortuem, K M, Egan, J B, Zhu, Y X, Xin, C S, Tiedemann, R E, Palmer, S E, Garbitt, V M, McCauley, D, Kauffman, M, Shacham, S, Chesi, M, Bergsagel, P L, Stewart, A K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 631/154/555; 631/208/205/2138; 631/80/389; 692/699/67/1990/804; Acrylamides - pharmacology; Animals; Antimitotic agents; Antineoplastic agents; Apoptosis; Biological Transport - drug effects; c-Myc protein; Cancer Research; Cancer therapies; Care and treatment; Carrier proteins; Cell cycle; Cell division; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Clinical trials; Critical Care Medicine; Dosage and administration; Exportin 1 Protein; Gene expression; Gene Expression Profiling; Genes; Genetic aspects; Genome-Wide Association Study; Genomes; Hematology; Homology; Humans; Identification and classification; Inhibitors; Intensive; Internal Medicine; Karyopherins - drug effects; Karyopherins - genetics; Leukemia; Medical prognosis; Medicine; Medicine & Public Health; Mice; Monoclonal gammopathy; Multiple myeloma; Multiple Myeloma - genetics; Myc protein; Nuclear transport; Oncology; original-article; Patients; Penicillin; Plasma cells; Protein transport; Proteins; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Cytoplasmic and Nuclear - genetics; Reverse Transcriptase Polymerase Chain Reaction; Reverse transcription; RNA Interference; RNA transport; RNA-mediated interference; Smoldering; Thiazoles - pharmacology; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; United States > US; KPT-276; exportin; XPO1; Myeloma; CRM1; CRM1 Inhibitors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.172

RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells ( P <0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM ( P <0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1 . The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A ( CDC25A ) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.