Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

J. Schmidt, Esteban D Braggio, K. M. Kortuem, J. B. Egan, Y. X. Zhu, C. S. Xin, R. E. Tiedemann, S. E. Palmer, V. M. Garbitt, D. McCauley, M. Kauffman, S. Shacham, Marta Chesi, Peter Leif Bergsagel, Alexander Keith Stewart

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2357-2365
Number of pages9
JournalLeukemia
Volume27
Issue number12
DOIs
StatePublished - Dec 2013

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Cell Nucleus Active Transport
Multiple Myeloma
Genome
Cell Cycle
Monoclonal Gammopathy of Undetermined Significance
KPT-276
Cell Line
Clinical Trials, Phase I
Hematologic Neoplasms
Nuclear Proteins
RNA Interference
Plasma Cells
Heterografts
Reverse Transcription
Disease Progression
Proteins
Down-Regulation
Western Blotting
Apoptosis
Gene Expression

Keywords

  • CRM1
  • CRM1 Inhibitors
  • exportin
  • KPT-276
  • Myeloma
  • XPO1

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. / Schmidt, J.; Braggio, Esteban D; Kortuem, K. M.; Egan, J. B.; Zhu, Y. X.; Xin, C. S.; Tiedemann, R. E.; Palmer, S. E.; Garbitt, V. M.; McCauley, D.; Kauffman, M.; Shacham, S.; Chesi, Marta; Bergsagel, Peter Leif; Stewart, Alexander Keith.

In: Leukemia, Vol. 27, No. 12, 12.2013, p. 2357-2365.

Research output: Contribution to journalArticle

Schmidt, J, Braggio, ED, Kortuem, KM, Egan, JB, Zhu, YX, Xin, CS, Tiedemann, RE, Palmer, SE, Garbitt, VM, McCauley, D, Kauffman, M, Shacham, S, Chesi, M, Bergsagel, PL & Stewart, AK 2013, 'Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276', Leukemia, vol. 27, no. 12, pp. 2357-2365. https://doi.org/10.1038/leu.2013.172
Schmidt, J. ; Braggio, Esteban D ; Kortuem, K. M. ; Egan, J. B. ; Zhu, Y. X. ; Xin, C. S. ; Tiedemann, R. E. ; Palmer, S. E. ; Garbitt, V. M. ; McCauley, D. ; Kauffman, M. ; Shacham, S. ; Chesi, Marta ; Bergsagel, Peter Leif ; Stewart, Alexander Keith. / Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. In: Leukemia. 2013 ; Vol. 27, No. 12. pp. 2357-2365.
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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.",
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T1 - Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

AU - Schmidt, J.

AU - Braggio, Esteban D

AU - Kortuem, K. M.

AU - Egan, J. B.

AU - Zhu, Y. X.

AU - Xin, C. S.

AU - Tiedemann, R. E.

AU - Palmer, S. E.

AU - Garbitt, V. M.

AU - McCauley, D.

AU - Kauffman, M.

AU - Shacham, S.

AU - Chesi, Marta

AU - Bergsagel, Peter Leif

AU - Stewart, Alexander Keith

PY - 2013/12

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N2 - 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.

AB - 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.

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