title: XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells.
abstract: Previous work has shown that the three-dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT-185, KPT-330/selinexor, and KPT-8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment-naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non-lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. J. Cell. Physiol. 231: 2711-2719, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Taylor-Kashton
authors.affiliation: Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lichtensztejn
authors.affiliation: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kauffman
authors.affiliation: CancerCare Manitoba, Winnipeg, Canada.
authors.forename: Rami
authors.initials: R
authors.lastname: Kotb
authors.affiliation: Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D028884:Karyopherins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein