Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice
Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ∼ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is a...
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| Veröffentlicht in: | Blood 2012-08, Vol.120 (5), p.1027-1038 |
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| creator | Kriss, Crystina L. Pinilla-Ibarz, Javier A. Mailloux, Adam W. Powers, John J. Tang, Chih-Hang Anthony Kang, Chang Won Zanesi, Nicola Epling-Burnette, Pearlie K. Sotomayor, Eduardo M. Croce, Carlo M. Del Valle, Juan R. Hu, Chih-Chi Andrew |
| description | Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ∼ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in Eμ-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Igα and Igβ, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL. |
| doi_str_mv | 10.1182/blood-2011-11-394346 |
| format | Article |
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TCL1 is expressed in ∼ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in Eμ-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Igα and Igβ, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-11-394346</identifier><identifier>PMID: 22692508</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; B-Lymphocytes - metabolism ; B-Lymphocytes - pathology ; Biological and medical sciences ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Endoplasmic Reticulum Stress - genetics ; Gene Expression Regulation, Leukemic ; Hematologic and hematopoietic diseases ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphoid Neoplasia ; Medical sciences ; Mice ; Mice, Transgenic ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - physiology ; Proto-Oncogene Proteins c-bcr - genetics ; Proto-Oncogene Proteins c-bcr - metabolism ; Proto-Oncogene Proteins c-bcr - physiology ; Time Factors ; Up-Regulation - genetics ; Up-Regulation - physiology</subject><ispartof>Blood, 2012-08, Vol.120 (5), p.1027-1038</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2012 by The American Society of Hematology 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-2c73347de33ef7baca145c33817a3157c7dcbb1d60920b50445f54f1b8d1a5b53</citedby><cites>FETCH-LOGICAL-c493t-2c73347de33ef7baca145c33817a3157c7dcbb1d60920b50445f54f1b8d1a5b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26200690$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22692508$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kriss, Crystina L.</creatorcontrib><creatorcontrib>Pinilla-Ibarz, Javier A.</creatorcontrib><creatorcontrib>Mailloux, Adam W.</creatorcontrib><creatorcontrib>Powers, John J.</creatorcontrib><creatorcontrib>Tang, Chih-Hang Anthony</creatorcontrib><creatorcontrib>Kang, Chang Won</creatorcontrib><creatorcontrib>Zanesi, Nicola</creatorcontrib><creatorcontrib>Epling-Burnette, Pearlie K.</creatorcontrib><creatorcontrib>Sotomayor, Eduardo M.</creatorcontrib><creatorcontrib>Croce, Carlo M.</creatorcontrib><creatorcontrib>Del Valle, Juan R.</creatorcontrib><creatorcontrib>Hu, Chih-Chi Andrew</creatorcontrib><title>Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice</title><title>Blood</title><addtitle>Blood</addtitle><description>Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ∼ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in Eμ-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Igα and Igβ, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL.</description><subject>Animals</subject><subject>B-Lymphocytes - metabolism</subject><subject>B-Lymphocytes - pathology</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Endoplasmic Reticulum Stress - genetics</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphoid Neoplasia</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Proto-Oncogene Proteins c-bcr - genetics</subject><subject>Proto-Oncogene Proteins c-bcr - metabolism</subject><subject>Proto-Oncogene Proteins c-bcr - physiology</subject><subject>Time Factors</subject><subject>Up-Regulation - genetics</subject><subject>Up-Regulation - physiology</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1DAUhS0EokPhHyDkDRKbgK8febBAqkblIY3UTVlbjnPTMTh2sJMRLPjvTZhpCxskS5avzzn32h8hL4G9Baj5u9bH2BWcARTLEo0UsnxENqB4XTDG2WOyYYyVhWwqOCPPcv7GGEjB1VNyxnnZcMXqDfl9dcCEP8eEObsYaOzp9XYH1NjJHcyEmU57pBi6OHqTB2dpwsnZ2c8DzdPqWgp5jCHje2poiAf0dEC7N8HlYY3zOH_H1TimeHPXxgW6lPA5edIbn_HFaT8nXz9eXm8_F7urT1-2F7vCykZMBbeVELLqUAjsq9ZYA1JZIWqojABV2aqzbQtdyRrOWsWkVL2SPbR1B0a1SpyTD8fccW4H7CyGKRmvx-QGk37paJz-9ya4vb6JBy3KmjFZLgFvTgEp_pgxT3pw2aL3JmCcswYmAEqoqlUqj1KbYs4J-_s2wPRKTv8hp1dyy1kfyS22V3-PeG-6Q7UIXp8EJlvj-2SCdflBV_KFdsMe3orLhx4cJp2tw2CxcwntpLvo_j_JLcd_urk</recordid><startdate>20120802</startdate><enddate>20120802</enddate><creator>Kriss, Crystina L.</creator><creator>Pinilla-Ibarz, Javier A.</creator><creator>Mailloux, Adam W.</creator><creator>Powers, John J.</creator><creator>Tang, Chih-Hang Anthony</creator><creator>Kang, Chang Won</creator><creator>Zanesi, Nicola</creator><creator>Epling-Burnette, Pearlie K.</creator><creator>Sotomayor, Eduardo M.</creator><creator>Croce, Carlo M.</creator><creator>Del Valle, Juan R.</creator><creator>Hu, Chih-Chi Andrew</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120802</creationdate><title>Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice</title><author>Kriss, Crystina L. ; Pinilla-Ibarz, Javier A. ; Mailloux, Adam W. ; Powers, John J. ; Tang, Chih-Hang Anthony ; Kang, Chang Won ; Zanesi, Nicola ; Epling-Burnette, Pearlie K. ; Sotomayor, Eduardo M. ; Croce, Carlo M. ; Del Valle, Juan R. ; Hu, Chih-Chi Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-2c73347de33ef7baca145c33817a3157c7dcbb1d60920b50445f54f1b8d1a5b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>B-Lymphocytes - metabolism</topic><topic>B-Lymphocytes - pathology</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Endoplasmic Reticulum Stress - genetics</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics</topic><topic>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphoid Neoplasia</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - physiology</topic><topic>Proto-Oncogene Proteins c-bcr - genetics</topic><topic>Proto-Oncogene Proteins c-bcr - metabolism</topic><topic>Proto-Oncogene Proteins c-bcr - physiology</topic><topic>Time Factors</topic><topic>Up-Regulation - genetics</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kriss, Crystina L.</creatorcontrib><creatorcontrib>Pinilla-Ibarz, Javier A.</creatorcontrib><creatorcontrib>Mailloux, Adam W.</creatorcontrib><creatorcontrib>Powers, John J.</creatorcontrib><creatorcontrib>Tang, Chih-Hang Anthony</creatorcontrib><creatorcontrib>Kang, Chang Won</creatorcontrib><creatorcontrib>Zanesi, Nicola</creatorcontrib><creatorcontrib>Epling-Burnette, Pearlie K.</creatorcontrib><creatorcontrib>Sotomayor, Eduardo M.</creatorcontrib><creatorcontrib>Croce, Carlo M.</creatorcontrib><creatorcontrib>Del Valle, Juan R.</creatorcontrib><creatorcontrib>Hu, Chih-Chi Andrew</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect: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>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>Kriss, Crystina L.</au><au>Pinilla-Ibarz, Javier A.</au><au>Mailloux, Adam W.</au><au>Powers, John J.</au><au>Tang, Chih-Hang Anthony</au><au>Kang, Chang Won</au><au>Zanesi, Nicola</au><au>Epling-Burnette, Pearlie K.</au><au>Sotomayor, Eduardo M.</au><au>Croce, Carlo M.</au><au>Del Valle, Juan R.</au><au>Hu, Chih-Chi Andrew</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-08-02</date><risdate>2012</risdate><volume>120</volume><issue>5</issue><spage>1027</spage><epage>1038</epage><pages>1027-1038</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ∼ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in Eμ-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Igα and Igβ, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22692508</pmid><doi>10.1182/blood-2011-11-394346</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals B-Lymphocytes - metabolism B-Lymphocytes - pathology Biological and medical sciences Cells, Cultured Disease Models, Animal Disease Progression Endoplasmic Reticulum Stress - genetics Gene Expression Regulation, Leukemic Hematologic and hematopoietic diseases Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoid Neoplasia Medical sciences Mice Mice, Transgenic Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - physiology Proto-Oncogene Proteins c-bcr - genetics Proto-Oncogene Proteins c-bcr - metabolism Proto-Oncogene Proteins c-bcr - physiology Time Factors Up-Regulation - genetics Up-Regulation - physiology |
| title | Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice |
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