B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406
Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in...
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| Veröffentlicht in: | Blood 2009-07, Vol.114 (5), p.1029-1037 |
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| creator | Quiroga, Maite P. Balakrishnan, Kumudha Kurtova, Antonina V. Sivina, Mariela Keating, Michael J. Wierda, William G. Gandhi, Varsha Burger, Jan A. |
| description | Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL. |
| doi_str_mv | 10.1182/blood-2009-03-212837 |
| format | Article |
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The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2009-03-212837</identifier><identifier>PMID: 19491390</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Cell Adhesion Molecules - biosynthesis ; Cell Adhesion Molecules - genetics ; Cell Survival - drug effects ; Cell Survival - physiology ; Chemokine CCL3 - metabolism ; Chemokine CCL4 - metabolism ; Chemotaxis - drug effects ; Chemotaxis - physiology ; Coculture Techniques ; Drug Screening Assays, Antitumor ; Female ; Hematologic and hematopoietic diseases ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - physiology ; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphocyte Activation - drug effects ; Lymphoid Neoplasia ; Male ; Medical sciences ; Mice ; Middle Aged ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - metabolism ; Neoplasm Proteins - physiology ; Oxazines - pharmacology ; Protein Kinase Inhibitors - pharmacology ; Protein Processing, Post-Translational - drug effects ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - physiology ; Pyridines - pharmacology ; Receptors, Antigen, B-Cell - physiology ; Receptors, Chemokine - biosynthesis ; Receptors, Chemokine - genetics ; Signal Transduction - drug effects ; Stromal Cells - physiology ; Syk Kinase</subject><ispartof>Blood, 2009-07, Vol.114 (5), p.1029-1037</ispartof><rights>2009 American Society of Hematology</rights><rights>2009 INIST-CNRS</rights><rights>2009 by The American Society of Hematology 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-2dd184f856f0ade14cfde07f2d402a3987573ef79d6b2661bad9ef055aa096263</citedby><cites>FETCH-LOGICAL-c491t-2dd184f856f0ade14cfde07f2d402a3987573ef79d6b2661bad9ef055aa096263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21804233$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19491390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Quiroga, Maite P.</creatorcontrib><creatorcontrib>Balakrishnan, Kumudha</creatorcontrib><creatorcontrib>Kurtova, Antonina V.</creatorcontrib><creatorcontrib>Sivina, Mariela</creatorcontrib><creatorcontrib>Keating, Michael J.</creatorcontrib><creatorcontrib>Wierda, William G.</creatorcontrib><creatorcontrib>Gandhi, Varsha</creatorcontrib><creatorcontrib>Burger, Jan A.</creatorcontrib><title>B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406</title><title>Blood</title><addtitle>Blood</addtitle><description>Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion Molecules - biosynthesis</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - physiology</subject><subject>Chemokine CCL3 - metabolism</subject><subject>Chemokine CCL4 - metabolism</subject><subject>Chemotaxis - drug effects</subject><subject>Chemotaxis - physiology</subject><subject>Coculture Techniques</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - physiology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - enzymology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Lymphoid Neoplasia</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Neoplasm Proteins - physiology</subject><subject>Oxazines - pharmacology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - physiology</subject><subject>Pyridines - pharmacology</subject><subject>Receptors, Antigen, B-Cell - physiology</subject><subject>Receptors, Chemokine - biosynthesis</subject><subject>Receptors, Chemokine - genetics</subject><subject>Signal Transduction - drug effects</subject><subject>Stromal Cells - physiology</subject><subject>Syk Kinase</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd2KFDEQhRtR3HH1DURy452tlfS_F8K6rD-wIIheh0xS3V1uJhmSTMs8ky-5mZ1hV2-8SqBOnapTX1G85PCW8168W1vvTSkAhhKqUnDRV92jYsUb0ZcAAh4XKwBoy3ro-FnxLMZfALyuRPO0OONDPfBqgFXx52Op0VqmXKIJHQuocZt8YJEmpyy5iaGbldMYmZ6Dd6SZ3W-2s9f7dPjj7gY3pNidy4amoBJ5l_0Mi7uw0KLsexa3qGnM8qTChOng-pvSzBRzfkGb6xbz8LQPPpJDdkNORWTkZlpT3uYN-15D-7x4Miob8cXpPS9-frr6cfmlvP72-evlxXWpc6pUCmN4X499046gDPJajwahG4WpQahq6Lumq3DsBtOuRdvytTIDjtA0SsHQirY6Lz4cfbe79QaNRpeCsnIbaKPCXnpF8t-Ko1lOfpF5fDvUPBvURwOd88SA430vB3mAJ-_gyQM8CZU8wsttr_6e-9B0opUFr08CFbWyY8hcKN7rBO-hFlX1EADzlRbCIKMmzAwNZb5JGk__3-QWmzW-WA</recordid><startdate>20090730</startdate><enddate>20090730</enddate><creator>Quiroga, Maite P.</creator><creator>Balakrishnan, Kumudha</creator><creator>Kurtova, Antonina V.</creator><creator>Sivina, Mariela</creator><creator>Keating, Michael J.</creator><creator>Wierda, William G.</creator><creator>Gandhi, Varsha</creator><creator>Burger, Jan A.</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>5PM</scope></search><sort><creationdate>20090730</creationdate><title>B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406</title><author>Quiroga, Maite P. ; Balakrishnan, Kumudha ; Kurtova, Antonina V. ; Sivina, Mariela ; Keating, Michael J. ; Wierda, William G. ; Gandhi, Varsha ; Burger, Jan A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-2dd184f856f0ade14cfde07f2d402a3987573ef79d6b2661bad9ef055aa096263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Adhesion Molecules - biosynthesis</topic><topic>Cell Adhesion Molecules - genetics</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - physiology</topic><topic>Chemokine CCL3 - metabolism</topic><topic>Chemokine CCL4 - metabolism</topic><topic>Chemotaxis - drug effects</topic><topic>Chemotaxis - physiology</topic><topic>Coculture Techniques</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - physiology</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - enzymology</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>Leukemias. 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The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>19491390</pmid><doi>10.1182/blood-2009-03-212837</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Blood, 2009-07, Vol.114 (5), p.1029-1037 |
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| subjects | Adult Aged Aged, 80 and over Animals Antineoplastic Agents - pharmacology Biological and medical sciences Cell Adhesion Molecules - biosynthesis Cell Adhesion Molecules - genetics Cell Survival - drug effects Cell Survival - physiology Chemokine CCL3 - metabolism Chemokine CCL4 - metabolism Chemotaxis - drug effects Chemotaxis - physiology Coculture Techniques Drug Screening Assays, Antitumor Female Hematologic and hematopoietic diseases Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - physiology Leukemia, Lymphocytic, Chronic, B-Cell - enzymology Leukemia, Lymphocytic, Chronic, B-Cell - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphocyte Activation - drug effects Lymphoid Neoplasia Male Medical sciences Mice Middle Aged Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - metabolism Neoplasm Proteins - physiology Oxazines - pharmacology Protein Kinase Inhibitors - pharmacology Protein Processing, Post-Translational - drug effects Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - physiology Pyridines - pharmacology Receptors, Antigen, B-Cell - physiology Receptors, Chemokine - biosynthesis Receptors, Chemokine - genetics Signal Transduction - drug effects Stromal Cells - physiology Syk Kinase |
| title | B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406 |
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