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Prognostic impact and targeting of CRM1 in acute myeloid leukemia
Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects...
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| Published in: | Blood 2013-05, Vol.121 (20), p.4166-4174 |
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| creator | Kojima, Kensuke Kornblau, Steven M. Ruvolo, Vivian Dilip, Archana Duvvuri, Seshagiri Davis, R. Eric Zhang, Min Wang, Zhiqiang Coombes, Kevin R. Zhang, Nianxiang Qiu, Yi Hua Burks, Jared K. Kantarjian, Hagop Shacham, Sharon Kauffman, Michael Andreeff, Michael |
| description | Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD34+/CD38– AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition.
•High CRM1 expression was associated with short survival of AML patients.•CRM1 inhibitor KPT-185 induces apoptosis mainly in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. |
| doi_str_mv | 10.1182/blood-2012-08-447581 |
| format | article |
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•High CRM1 expression was associated with short survival of AML patients.•CRM1 inhibitor KPT-185 induces apoptosis mainly in a p53-dependent manner, whereas inhibition of proliferation was p53 independent.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2012-08-447581</identifier><identifier>PMID: 23564911</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acrylates - therapeutic use ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - physiology ; Cells, Cultured ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm - genetics ; Exportin 1 Protein ; Female ; HL-60 Cells ; Humans ; Karyopherins - antagonists & inhibitors ; Karyopherins - genetics ; Karyopherins - physiology ; Leukemia, Myeloid, Acute - diagnosis ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Male ; Molecular Targeted Therapy ; Myeloid Neoplasia ; Prognosis ; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors ; Receptors, Cytoplasmic and Nuclear - genetics ; Receptors, Cytoplasmic and Nuclear - physiology ; Triazoles - therapeutic use ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Protein p53 - physiology ; U937 Cells</subject><ispartof>Blood, 2013-05, Vol.121 (20), p.4166-4174</ispartof><rights>2013 American Society of Hematology</rights><rights>2013 by The American Society of Hematology 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-9331e1b35fb14888e12fe0fc70f51092ad08c18b5293c19eb6f8a62285c62a8d3</citedby><cites>FETCH-LOGICAL-c529t-9331e1b35fb14888e12fe0fc70f51092ad08c18b5293c19eb6f8a62285c62a8d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006497120585054$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,786,790,891,3568,27957,27958,45815</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23564911$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kojima, Kensuke</creatorcontrib><creatorcontrib>Kornblau, Steven M.</creatorcontrib><creatorcontrib>Ruvolo, Vivian</creatorcontrib><creatorcontrib>Dilip, Archana</creatorcontrib><creatorcontrib>Duvvuri, Seshagiri</creatorcontrib><creatorcontrib>Davis, R. Eric</creatorcontrib><creatorcontrib>Zhang, Min</creatorcontrib><creatorcontrib>Wang, Zhiqiang</creatorcontrib><creatorcontrib>Coombes, Kevin R.</creatorcontrib><creatorcontrib>Zhang, Nianxiang</creatorcontrib><creatorcontrib>Qiu, Yi Hua</creatorcontrib><creatorcontrib>Burks, Jared K.</creatorcontrib><creatorcontrib>Kantarjian, Hagop</creatorcontrib><creatorcontrib>Shacham, Sharon</creatorcontrib><creatorcontrib>Kauffman, Michael</creatorcontrib><creatorcontrib>Andreeff, Michael</creatorcontrib><title>Prognostic impact and targeting of CRM1 in acute myeloid leukemia</title><title>Blood</title><addtitle>Blood</addtitle><description>Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD34+/CD38– AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition.
•High CRM1 expression was associated with short survival of AML patients.•CRM1 inhibitor KPT-185 induces apoptosis mainly in a p53-dependent manner, whereas inhibition of proliferation was p53 independent.</description><subject>Acrylates - therapeutic use</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - physiology</subject><subject>Cells, Cultured</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Exportin 1 Protein</subject><subject>Female</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Karyopherins - antagonists & inhibitors</subject><subject>Karyopherins - genetics</subject><subject>Karyopherins - physiology</subject><subject>Leukemia, Myeloid, Acute - diagnosis</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Male</subject><subject>Molecular Targeted Therapy</subject><subject>Myeloid Neoplasia</subject><subject>Prognosis</subject><subject>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - physiology</subject><subject>Triazoles - therapeutic use</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Protein p53 - physiology</subject><subject>U937 Cells</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kEtP3TAQhS3UCi6Pf4AqL7sJzNhxrrOphK54SVStKlhbjjO5dUniW9tB4t83cHm0m65mMeecmfMxdoxwgqjFadOH0BYCUBSgi7JcKo07bIFK6AJAwAe2AICqKOsl7rH9lH4BYCmF2mV7QqqqrBEX7Ox7DOsxpOwd98PGuszt2PJs45qyH9c8dHz14ytyP3Lrpkx8eKQ--Jb3NN3T4O0h-9jZPtHRyzxgdxfnt6ur4ubb5fXq7KZwStS5qKVEwkaqrsFSa00oOoLOLaFTCLWwLWiHupnF0mFNTdVpWwmhlauE1a08YF-2uZupGah1NOZoe7OJfrDx0QTrzb-b0f806_BgZDWXVTgHfH4JiOH3RCmbwSdHfW9HClMyKJWEUoilnqXlVupiSClS93YGwTzRN8_0zRN9A9ps6c-2T3-_-GZ6xf3egWZQD56iSc7T6Kj1kVw2bfD_v_AHlfyWTg</recordid><startdate>20130516</startdate><enddate>20130516</enddate><creator>Kojima, Kensuke</creator><creator>Kornblau, Steven M.</creator><creator>Ruvolo, Vivian</creator><creator>Dilip, Archana</creator><creator>Duvvuri, Seshagiri</creator><creator>Davis, R. Eric</creator><creator>Zhang, Min</creator><creator>Wang, Zhiqiang</creator><creator>Coombes, Kevin R.</creator><creator>Zhang, Nianxiang</creator><creator>Qiu, Yi Hua</creator><creator>Burks, Jared K.</creator><creator>Kantarjian, Hagop</creator><creator>Shacham, Sharon</creator><creator>Kauffman, Michael</creator><creator>Andreeff, Michael</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130516</creationdate><title>Prognostic impact and targeting of CRM1 in acute myeloid leukemia</title><author>Kojima, Kensuke ; Kornblau, Steven M. ; Ruvolo, Vivian ; Dilip, Archana ; Duvvuri, Seshagiri ; Davis, R. Eric ; Zhang, Min ; Wang, Zhiqiang ; Coombes, Kevin R. ; Zhang, Nianxiang ; Qiu, Yi Hua ; Burks, Jared K. ; Kantarjian, Hagop ; Shacham, Sharon ; Kauffman, Michael ; Andreeff, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-9331e1b35fb14888e12fe0fc70f51092ad08c18b5293c19eb6f8a62285c62a8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acrylates - therapeutic use</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - physiology</topic><topic>Cells, Cultured</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Exportin 1 Protein</topic><topic>Female</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Karyopherins - antagonists & inhibitors</topic><topic>Karyopherins - genetics</topic><topic>Karyopherins - physiology</topic><topic>Leukemia, Myeloid, Acute - diagnosis</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Male</topic><topic>Molecular Targeted Therapy</topic><topic>Myeloid Neoplasia</topic><topic>Prognosis</topic><topic>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - physiology</topic><topic>Triazoles - therapeutic use</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Protein p53 - physiology</topic><topic>U937 Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kojima, Kensuke</creatorcontrib><creatorcontrib>Kornblau, Steven M.</creatorcontrib><creatorcontrib>Ruvolo, Vivian</creatorcontrib><creatorcontrib>Dilip, Archana</creatorcontrib><creatorcontrib>Duvvuri, Seshagiri</creatorcontrib><creatorcontrib>Davis, R. Eric</creatorcontrib><creatorcontrib>Zhang, Min</creatorcontrib><creatorcontrib>Wang, Zhiqiang</creatorcontrib><creatorcontrib>Coombes, Kevin R.</creatorcontrib><creatorcontrib>Zhang, Nianxiang</creatorcontrib><creatorcontrib>Qiu, Yi Hua</creatorcontrib><creatorcontrib>Burks, Jared K.</creatorcontrib><creatorcontrib>Kantarjian, Hagop</creatorcontrib><creatorcontrib>Shacham, Sharon</creatorcontrib><creatorcontrib>Kauffman, Michael</creatorcontrib><creatorcontrib>Andreeff, Michael</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kojima, Kensuke</au><au>Kornblau, Steven M.</au><au>Ruvolo, Vivian</au><au>Dilip, Archana</au><au>Duvvuri, Seshagiri</au><au>Davis, R. Eric</au><au>Zhang, Min</au><au>Wang, Zhiqiang</au><au>Coombes, Kevin R.</au><au>Zhang, Nianxiang</au><au>Qiu, Yi Hua</au><au>Burks, Jared K.</au><au>Kantarjian, Hagop</au><au>Shacham, Sharon</au><au>Kauffman, Michael</au><au>Andreeff, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prognostic impact and targeting of CRM1 in acute myeloid leukemia</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2013-05-16</date><risdate>2013</risdate><volume>121</volume><issue>20</issue><spage>4166</spage><epage>4174</epage><pages>4166-4174</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD34+/CD38– AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition.
•High CRM1 expression was associated with short survival of AML patients.•CRM1 inhibitor KPT-185 induces apoptosis mainly in a p53-dependent manner, whereas inhibition of proliferation was p53 independent.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23564911</pmid><doi>10.1182/blood-2012-08-447581</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acrylates - therapeutic use Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics Biomarkers, Tumor - physiology Cells, Cultured Drug Evaluation, Preclinical Drug Resistance, Neoplasm - genetics Exportin 1 Protein Female HL-60 Cells Humans Karyopherins - antagonists & inhibitors Karyopherins - genetics Karyopherins - physiology Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Male Molecular Targeted Therapy Myeloid Neoplasia Prognosis Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - physiology Triazoles - therapeutic use Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Protein p53 - physiology U937 Cells |
| title | Prognostic impact and targeting of CRM1 in acute myeloid leukemia |
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