title: Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Schmidt
authors.forename: E
authors.initials: E
authors.lastname: Braggio
authors.forename: K M
authors.initials: KM
authors.lastname: Kortuem
authors.forename: J B
authors.initials: JB
authors.lastname: Egan
authors.forename: Y X
authors.initials: YX
authors.lastname: Zhu
authors.forename: C S
authors.initials: CS
authors.lastname: Xin
authors.forename: R E
authors.initials: RE
authors.lastname: Tiedemann
authors.forename: S E
authors.initials: SE
authors.lastname: Palmer
authors.forename: V M
authors.initials: VM
authors.lastname: Garbitt
authors.forename: D
authors.initials: D
authors.lastname: McCauley
authors.forename: M
authors.initials: M
authors.lastname: Kauffman
authors.forename: S
authors.initials: S
authors.lastname: Shacham
authors.forename: M
authors.initials: M
authors.lastname: Chesi
authors.forename: P L
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: A K
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D028884:Karyopherins / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000178:Acrylamides; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D000097606:Exportin 1 Protein; C586831:KPT-276