Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity
Summary Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cer...
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| Veröffentlicht in: | British journal of haematology 2014-01, Vol.164 (2), p.233-244 |
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| creator | Gandhi, Anita K. Mendy, Derek Waldman, Michelle Chen, Gengxin Rychak, Emily Miller, Karen Gaidarova, Svetlana Ren, Yan Wang, Maria Breider, Michael Carmel, Gilles Mahmoudi, Afshin Jackson, Pilgrim Abbasian, Mahan Cathers, Brian E. Schafer, Peter H. Daniel, Tom O. Lopez‐Girona, Antonia Thakurta, Anjan Chopra, Rajesh |
| description | Summary
Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cereblon's central role as a target of lenalidomide and pomalidomide suggests potential utility as a predictive biomarker of response or resistance to IMiD therapy. Our studies characterized a cereblon monoclonal antibody CRBN65, with high sensitivity and specificity in Western analysis and immunohistochemistry that is superior to commercially available antibodies. We identified multiple cereblon splice variants in both MM cell lines and primary cells, highlighting challenges with conventional gene expression assays given this gene complexity. Using CRBN65 antibody and TaqMan quantitative reverse transcription polymerase chain reaction assays, we showed lack of correlation between cereblon protein and mRNA levels. Furthermore, lack of correlation between cereblon expression in MM cell lines and sensitivity to lenalidomide was shown. In cell lines made resistant to lenalidomide and pomalidomide, cereblon protein is greatly reduced. These studies show limitations to the current approaches of cereblon measurement that rely on commercial reagents and assays. Standardized reagents and validated assays are needed to accurately assess the role of cereblon as a predictive biomarker. |
| doi_str_mv | 10.1111/bjh.12622 |
| format | Article |
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Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cereblon's central role as a target of lenalidomide and pomalidomide suggests potential utility as a predictive biomarker of response or resistance to IMiD therapy. Our studies characterized a cereblon monoclonal antibody CRBN65, with high sensitivity and specificity in Western analysis and immunohistochemistry that is superior to commercially available antibodies. We identified multiple cereblon splice variants in both MM cell lines and primary cells, highlighting challenges with conventional gene expression assays given this gene complexity. Using CRBN65 antibody and TaqMan quantitative reverse transcription polymerase chain reaction assays, we showed lack of correlation between cereblon protein and mRNA levels. Furthermore, lack of correlation between cereblon expression in MM cell lines and sensitivity to lenalidomide was shown. In cell lines made resistant to lenalidomide and pomalidomide, cereblon protein is greatly reduced. These studies show limitations to the current approaches of cereblon measurement that rely on commercial reagents and assays. Standardized reagents and validated assays are needed to accurately assess the role of cereblon as a predictive biomarker.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/bjh.12622</identifier><identifier>PMID: 24206017</identifier><identifier>CODEN: BJHEAL</identifier><language>eng</language><publisher>Oxford: Blackwell</publisher><subject>Adaptor Proteins, Signal Transducing ; Alternative Splicing ; Antibodies, Monoclonal - immunology ; Antibody Specificity - immunology ; Biological and medical sciences ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cell Line, Tumor ; cereblon ; cullin 4 ring ligase complex ; DNA damage binding protein 1 ; Drug Resistance, Neoplasm - genetics ; Haematological Malignancy ; Hematologic and hematopoietic diseases ; Humans ; immunomodulatory drugs ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Multiple Myeloma - drug therapy ; Multiple Myeloma - genetics ; Multiple Myeloma - metabolism ; myeloma ; Peptide Hydrolases - genetics ; Peptide Hydrolases - immunology ; Peptide Hydrolases - metabolism ; RNA Isoforms ; Thalidomide - analogs & derivatives ; Thalidomide - pharmacology ; Thalidomide - therapeutic use ; Tumors ; Ubiquitin-Protein Ligases</subject><ispartof>British journal of haematology, 2014-01, Vol.164 (2), p.233-244</ispartof><rights>2013 Celgene Corporation. published by John Wiley & Sons Ltd.</rights><rights>2015 INIST-CNRS</rights><rights>2013 Celgene Corporation. British Journal of Haematology published by John Wiley & Sons Ltd.</rights><rights>2013 Celgene Corporation. published by John Wiley & Sons Ltd. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5442-cbde3e71ae78819eaa27a0e0bffb5671f7e7bc50309dd070f2537af92eaddb0d3</citedby><cites>FETCH-LOGICAL-c5442-cbde3e71ae78819eaa27a0e0bffb5671f7e7bc50309dd070f2537af92eaddb0d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbjh.12622$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjh.12622$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28318664$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24206017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gandhi, Anita K.</creatorcontrib><creatorcontrib>Mendy, Derek</creatorcontrib><creatorcontrib>Waldman, Michelle</creatorcontrib><creatorcontrib>Chen, Gengxin</creatorcontrib><creatorcontrib>Rychak, Emily</creatorcontrib><creatorcontrib>Miller, Karen</creatorcontrib><creatorcontrib>Gaidarova, Svetlana</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Wang, Maria</creatorcontrib><creatorcontrib>Breider, Michael</creatorcontrib><creatorcontrib>Carmel, Gilles</creatorcontrib><creatorcontrib>Mahmoudi, Afshin</creatorcontrib><creatorcontrib>Jackson, Pilgrim</creatorcontrib><creatorcontrib>Abbasian, Mahan</creatorcontrib><creatorcontrib>Cathers, Brian E.</creatorcontrib><creatorcontrib>Schafer, Peter H.</creatorcontrib><creatorcontrib>Daniel, Tom O.</creatorcontrib><creatorcontrib>Lopez‐Girona, Antonia</creatorcontrib><creatorcontrib>Thakurta, Anjan</creatorcontrib><creatorcontrib>Chopra, Rajesh</creatorcontrib><title>Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cereblon's central role as a target of lenalidomide and pomalidomide suggests potential utility as a predictive biomarker of response or resistance to IMiD therapy. Our studies characterized a cereblon monoclonal antibody CRBN65, with high sensitivity and specificity in Western analysis and immunohistochemistry that is superior to commercially available antibodies. We identified multiple cereblon splice variants in both MM cell lines and primary cells, highlighting challenges with conventional gene expression assays given this gene complexity. Using CRBN65 antibody and TaqMan quantitative reverse transcription polymerase chain reaction assays, we showed lack of correlation between cereblon protein and mRNA levels. Furthermore, lack of correlation between cereblon expression in MM cell lines and sensitivity to lenalidomide was shown. In cell lines made resistant to lenalidomide and pomalidomide, cereblon protein is greatly reduced. These studies show limitations to the current approaches of cereblon measurement that rely on commercial reagents and assays. Standardized reagents and validated assays are needed to accurately assess the role of cereblon as a predictive biomarker.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Alternative Splicing</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibody Specificity - immunology</subject><subject>Biological and medical sciences</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Line, Tumor</subject><subject>cereblon</subject><subject>cullin 4 ring ligase complex</subject><subject>DNA damage binding protein 1</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Haematological Malignancy</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>immunomodulatory drugs</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - metabolism</subject><subject>myeloma</subject><subject>Peptide Hydrolases - genetics</subject><subject>Peptide Hydrolases - immunology</subject><subject>Peptide Hydrolases - metabolism</subject><subject>RNA Isoforms</subject><subject>Thalidomide - analogs & derivatives</subject><subject>Thalidomide - pharmacology</subject><subject>Thalidomide - therapeutic use</subject><subject>Tumors</subject><subject>Ubiquitin-Protein Ligases</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAUhS0EokNhwQsgb5BgkdZ2fmeDBBVQUBEbWFs39vXUxbFTOwGGF-I1cWaGARZ4E8vnO_dc5RDymLMzns95f3N9xkUjxB2y4mVTF4JX_C5ZMcbagrOqOyEPUrphjJes5vfJiagEaxhvV-TnB4Q0R-s3VGHE3gVPIVGgvQ0DxC8YaTA0YhqDT0hDXO42TeAV0ilQhx6c1WGwGil4TcdsOz5EvJ1tNtB58Rq6-DREbX-gziJs0E9pZ5u9xriTl1UymiWkKgyjw-922j4k9wy4hI8O31Py-c3rTxeXxdXHt-8uXl4Vqq4qUaheY4ktB2y7jq8RQLTAkPXG9HXTctNi26ualWytNWuZEXXZglkLBK17pstT8mI_d5z7AbXKC0Zwcow2_42tDGDlv4q313ITvsoqT2JdnQc8OwyI4XbGNMnBJoXOgccwJ8nrsupExesqo8_3qIohpYjmGMOZXIqVuVi5KzazT_7e60j-bjIDTw8AJAXOxNyQTX-4ruRd0yyh53vum3W4_X-ifPX-ch_9C4wUwEg</recordid><startdate>201401</startdate><enddate>201401</enddate><creator>Gandhi, Anita K.</creator><creator>Mendy, Derek</creator><creator>Waldman, Michelle</creator><creator>Chen, Gengxin</creator><creator>Rychak, Emily</creator><creator>Miller, Karen</creator><creator>Gaidarova, Svetlana</creator><creator>Ren, Yan</creator><creator>Wang, Maria</creator><creator>Breider, Michael</creator><creator>Carmel, Gilles</creator><creator>Mahmoudi, Afshin</creator><creator>Jackson, Pilgrim</creator><creator>Abbasian, Mahan</creator><creator>Cathers, Brian E.</creator><creator>Schafer, Peter H.</creator><creator>Daniel, Tom O.</creator><creator>Lopez‐Girona, Antonia</creator><creator>Thakurta, Anjan</creator><creator>Chopra, Rajesh</creator><general>Blackwell</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>IQODW</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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201401</creationdate><title>Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity</title><author>Gandhi, Anita K. ; Mendy, Derek ; Waldman, Michelle ; Chen, Gengxin ; Rychak, Emily ; Miller, Karen ; Gaidarova, Svetlana ; Ren, Yan ; Wang, Maria ; Breider, Michael ; Carmel, Gilles ; Mahmoudi, Afshin ; Jackson, Pilgrim ; Abbasian, Mahan ; Cathers, Brian E. ; Schafer, Peter H. ; Daniel, Tom O. ; Lopez‐Girona, Antonia ; Thakurta, Anjan ; Chopra, Rajesh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5442-cbde3e71ae78819eaa27a0e0bffb5671f7e7bc50309dd070f2537af92eaddb0d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Alternative Splicing</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibody Specificity - immunology</topic><topic>Biological and medical sciences</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Line, Tumor</topic><topic>cereblon</topic><topic>cullin 4 ring ligase complex</topic><topic>DNA damage binding protein 1</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Haematological Malignancy</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>immunomodulatory drugs</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - genetics</topic><topic>Multiple Myeloma - metabolism</topic><topic>myeloma</topic><topic>Peptide Hydrolases - genetics</topic><topic>Peptide Hydrolases - immunology</topic><topic>Peptide Hydrolases - metabolism</topic><topic>RNA Isoforms</topic><topic>Thalidomide - analogs & derivatives</topic><topic>Thalidomide - pharmacology</topic><topic>Thalidomide - therapeutic use</topic><topic>Tumors</topic><topic>Ubiquitin-Protein Ligases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gandhi, Anita K.</creatorcontrib><creatorcontrib>Mendy, Derek</creatorcontrib><creatorcontrib>Waldman, Michelle</creatorcontrib><creatorcontrib>Chen, Gengxin</creatorcontrib><creatorcontrib>Rychak, Emily</creatorcontrib><creatorcontrib>Miller, Karen</creatorcontrib><creatorcontrib>Gaidarova, Svetlana</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Wang, Maria</creatorcontrib><creatorcontrib>Breider, Michael</creatorcontrib><creatorcontrib>Carmel, Gilles</creatorcontrib><creatorcontrib>Mahmoudi, Afshin</creatorcontrib><creatorcontrib>Jackson, Pilgrim</creatorcontrib><creatorcontrib>Abbasian, Mahan</creatorcontrib><creatorcontrib>Cathers, Brian E.</creatorcontrib><creatorcontrib>Schafer, Peter H.</creatorcontrib><creatorcontrib>Daniel, Tom O.</creatorcontrib><creatorcontrib>Lopez‐Girona, Antonia</creatorcontrib><creatorcontrib>Thakurta, Anjan</creatorcontrib><creatorcontrib>Chopra, Rajesh</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gandhi, Anita K.</au><au>Mendy, Derek</au><au>Waldman, Michelle</au><au>Chen, Gengxin</au><au>Rychak, Emily</au><au>Miller, Karen</au><au>Gaidarova, Svetlana</au><au>Ren, Yan</au><au>Wang, Maria</au><au>Breider, Michael</au><au>Carmel, Gilles</au><au>Mahmoudi, Afshin</au><au>Jackson, Pilgrim</au><au>Abbasian, Mahan</au><au>Cathers, Brian E.</au><au>Schafer, Peter H.</au><au>Daniel, Tom O.</au><au>Lopez‐Girona, Antonia</au><au>Thakurta, Anjan</au><au>Chopra, Rajesh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2014-01</date><risdate>2014</risdate><volume>164</volume><issue>2</issue><spage>233</spage><epage>244</epage><pages>233-244</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><coden>BJHEAL</coden><abstract>Summary
Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cereblon's central role as a target of lenalidomide and pomalidomide suggests potential utility as a predictive biomarker of response or resistance to IMiD therapy. Our studies characterized a cereblon monoclonal antibody CRBN65, with high sensitivity and specificity in Western analysis and immunohistochemistry that is superior to commercially available antibodies. We identified multiple cereblon splice variants in both MM cell lines and primary cells, highlighting challenges with conventional gene expression assays given this gene complexity. Using CRBN65 antibody and TaqMan quantitative reverse transcription polymerase chain reaction assays, we showed lack of correlation between cereblon protein and mRNA levels. Furthermore, lack of correlation between cereblon expression in MM cell lines and sensitivity to lenalidomide was shown. In cell lines made resistant to lenalidomide and pomalidomide, cereblon protein is greatly reduced. These studies show limitations to the current approaches of cereblon measurement that rely on commercial reagents and assays. Standardized reagents and validated assays are needed to accurately assess the role of cereblon as a predictive biomarker.</abstract><cop>Oxford</cop><pub>Blackwell</pub><pmid>24206017</pmid><doi>10.1111/bjh.12622</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of haematology, 2014-01, Vol.164 (2), p.233-244 |
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| language | eng |
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| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adaptor Proteins, Signal Transducing Alternative Splicing Antibodies, Monoclonal - immunology Antibody Specificity - immunology Biological and medical sciences Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Line, Tumor cereblon cullin 4 ring ligase complex DNA damage binding protein 1 Drug Resistance, Neoplasm - genetics Haematological Malignancy Hematologic and hematopoietic diseases Humans immunomodulatory drugs Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Multiple Myeloma - drug therapy Multiple Myeloma - genetics Multiple Myeloma - metabolism myeloma Peptide Hydrolases - genetics Peptide Hydrolases - immunology Peptide Hydrolases - metabolism RNA Isoforms Thalidomide - analogs & derivatives Thalidomide - pharmacology Thalidomide - therapeutic use Tumors Ubiquitin-Protein Ligases |
| title | Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity |
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