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Title: Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia
Authors: Lapalombella, Rosa ×
Sun, Qingxiang
Williams, Katie
Tangeman, Larissa
Jha, Shruti
Zhong, Yiming
Goettl, Virginia
Mahoney, Emilia
Berglund, Caroline
Gupta, Sneha
Farmer, Alicia
Mani, Rajeswaran
Johnson, Amy J
Lucas, David
Mo, Xiaokui
Daelemans, Dirk
Sandanayaka, Vincent
Shechter, Sharon
McCauley, Dilara
Shacham, Sharon
Kauffman, Michael
Chook, Yuh Min
Byrd, John C #
Issue Date: Nov-2012
Publisher: W.B. Saunders
Series Title: Blood vol:120 issue:23 pages:4621-4634
Article number: 10.1182/blood-2012-05-429506
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.
URI: 
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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