{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:26:54Z","timestamp":1779114414719,"version":"3.51.4"},"reference-count":137,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C42023\/A29370"],"award-info":[{"award-number":["C42023\/A29370"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C24563\/A15581"],"award-info":[{"award-number":["C24563\/A15581"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C34999\/A18087"],"award-info":[{"award-number":["C34999\/A18087"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C2750\/A23669"],"award-info":[{"award-number":["C2750\/A23669"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C36811\/A29101"],"award-info":[{"award-number":["C36811\/A29101"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007903","name":"Blood Cancer UK","doi-asserted-by":"publisher","award":["18009"],"award-info":[{"award-number":["18009"]}],"id":[{"id":"10.13039\/501100007903","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.<\/jats:p>","DOI":"10.3390\/cancers14030663","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T01:41:59Z","timestamp":1643420519000},"page":"663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-1831","authenticated-orcid":false,"given":"Francesco","family":"Forconi","sequence":"first","affiliation":[{"name":"School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton SO16 6YD, UK"},{"name":"Department of Haematology, University Hospital Southampton NHS Trust, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart A.","family":"Lanham","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgia","family":"Chiodin","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1182\/blood.V43.6.789.789","article-title":"Comparison of normal and CLL lymphocyte surface Ig determinants using peroxidase-labeled antibodies. 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