title: Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.
abstract: The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Katie
authors.initials: K
authors.lastname: Williams
authors.forename: Larissa
authors.initials: L
authors.lastname: Tangeman
authors.forename: Shruti
authors.initials: S
authors.lastname: Jha
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.forename: Virginia
authors.initials: V
authors.lastname: Goettl
authors.forename: Emilia
authors.initials: E
authors.lastname: Mahoney
authors.forename: Caroline
authors.initials: C
authors.lastname: Berglund
authors.forename: Sneha
authors.initials: S
authors.lastname: Gupta
authors.forename: Alicia
authors.initials: A
authors.lastname: Farmer
authors.forename: Rajeswaran
authors.initials: R
authors.lastname: Mani
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Lucas
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.forename: Vincent
authors.initials: V
authors.lastname: Sandanayaka
authors.forename: Sharon
authors.initials: S
authors.lastname: Shechter
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: Yuh Min
authors.initials: YM
authors.lastname: Chook
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D015151:Immunoblotting; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D028884:Karyopherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D016753:Interleukin-10; D015850:Interleukin-6; D028884:Karyopherins; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C090851:TCL1A protein, human