{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T07:49:36Z","timestamp":1764402576664,"version":"3.40.2"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,1]],"date-time":"2013-08-01T00:00:00Z","timestamp":1375315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and \u03b1L\u03b22 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed \u03b1L\u03b22 activation and TEM unless \u03b14\u03b21 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation\/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation\/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1\/phospholipase D1\u2013mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.<\/jats:p>","DOI":"10.4049\/jimmunol.1203484","type":"journal-article","created":{"date-parts":[[2013,6,27]],"date-time":"2013-06-27T01:26:57Z","timestamp":1372296417000},"page":"1496-1504","source":"Crossref","is-referenced-by-count":13,"title":["Chemokine Unresponsiveness of Chronic Lymphocytic Leukemia Cells Results from Impaired Endosomal Recycling of Rap1 and Is Associated with a Distinctive Type of Immunological Anergy"],"prefix":"10.1093","volume":"191","author":[{"given":"Derek S","family":"Pye","sequence":"first","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool , Liverpool L69 3GA,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Rubio","sequence":"additional","affiliation":[{"name":"Institute for Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena , 07745 Jena,","place":["Germany"]},{"name":"Research Group ANERGY, Center for Sepsis Control and Care, University Hospital Jena , 07747 Jena,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rico","family":"Pusch","sequence":"additional","affiliation":[{"name":"Institute for Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena , 07745 Jena,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool , Liverpool L69 3GA,","place":["United Kingdom"]},{"name":"Department of Haematology, Royal Liverpool University Hospital , Liverpool L7 8XP,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R","family":"Pettitt","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool , Liverpool L69 3GA,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen J","family":"Till","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool , Liverpool L69 3GA,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,8,1]]},"reference":[{"key":"2025032405121718300_r1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1182\/blood.V46.2.219.219","article-title":"Clinical staging of chronic lymphocytic leukemia","volume":"46","author":"Rai","year":"1975","journal-title":"Blood"},{"key":"2025032405121718300_r2","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/1097-0142(197708)40:2<855::AID-CNCR2820400239>3.0.CO;2-1","article-title":"A clinical staging system for chronic lymphocytic leukemia: prognostic significance","volume":"40","author":"Binet","year":"1977","journal-title":"Cancer"},{"key":"2025032405121718300_r3","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1046\/j.1365-2141.2003.04679.x","article-title":"Role of the microenvironment in chronic lymphocytic leukaemia","volume":"123","author":"Caligaris-Cappio","year":"2003","journal-title":"Br. 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