Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Rosa Lapalombella, Qingxiang Sun, Katie Williams, Larissa Tangeman, Shruti Jha, Yiming Zhong, Virginia Goettl, Emilia Mahoney, Caroline Berglund, Sneha Gupta, Alicia Farmer, Rajeswaran Mani, Amy J. Johnson, David Lucas, Xiaokui Mo, Dirk Daelemans, Vincent Sandanayaka, Sharon Shechter, Dilara McCauley, Sharon Shacham & 3 others Michael Kauffman, Yuh Min Chook, John C. Byrd

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

The nuclear export protein XPO1 is over-expressed 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.

Original languageEnglish (US)
Pages (from-to)4621-4634
Number of pages14
JournalBlood
Volume120
Issue number23
DOIs
StatePublished - Nov 29 2012

Fingerprint

Cell Nucleus Active Transport
B-Cell Chronic Lymphocytic Leukemia
Toxicity
Tumor Suppressor Proteins
Cysteine
Apoptosis
X rays
Molecules
Proteins
Experiments
SCID Mice
Hematologic Neoplasms
Nuclear Proteins
Disease Progression
Weight Loss
X-Rays
Mutation
exportin 1 protein
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Lapalombella, R., Sun, Q., Williams, K., Tangeman, L., Jha, S., Zhong, Y., ... Byrd, J. C. (2012). Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood, 120(23), 4621-4634. https://doi.org/10.1182/blood-2012-05-429506

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. / 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.

In: Blood, Vol. 120, No. 23, 29.11.2012, p. 4621-4634.

Research output: Contribution to journalArticle

Lapalombella, R, Sun, Q, Williams, K, Tangeman, L, Jha, S, Zhong, Y, Goettl, V, Mahoney, E, Berglund, C, Gupta, S, Farmer, A, Mani, R, Johnson, AJ, Lucas, D, Mo, X, Daelemans, D, Sandanayaka, V, Shechter, S, McCauley, D, Shacham, S, Kauffman, M, Chook, YM & Byrd, JC 2012, 'Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia', Blood, vol. 120, no. 23, pp. 4621-4634. https://doi.org/10.1182/blood-2012-05-429506
Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012 Nov 29;120(23):4621-4634. https://doi.org/10.1182/blood-2012-05-429506
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. / Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. In: Blood. 2012 ; Vol. 120, No. 23. pp. 4621-4634.
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AU - Jha, Shruti

AU - Zhong, Yiming

AU - Goettl, Virginia

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AU - Mani, Rajeswaran

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AU - Sandanayaka, Vincent

AU - Shechter, Sharon

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AU - Byrd, John C.

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