{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:53:10Z","timestamp":1790963590914,"version":"4.1.0"},"reference-count":192,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/01383"],"award-info":[{"award-number":["PI18\/01383"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte\u2019s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton\u2019s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off\/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.<\/jats:p>","DOI":"10.3390\/cancers14040860","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T21:19:06Z","timestamp":1644441546000},"page":"860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8923-6025","authenticated-orcid":false,"given":"N\u00faria","family":"Profit\u00f3s-Pelej\u00e0","sequence":"first","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4148-9570","authenticated-orcid":false,"given":"Juliana Carvalho","family":"Santos","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7592-6815","authenticated-orcid":false,"given":"Ana","family":"Mar\u00edn-Niebla","sequence":"additional","affiliation":[{"name":"Department of Hematology, Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Vall d\u2019Hebron Barcelona Hospital Campus, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0245-2257","authenticated-orcid":false,"given":"Ga\u00ebl","family":"Rou\u00e9","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Lima","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"},{"name":"Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista 12916-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3322\/caac.21357","article-title":"2016 US lymphoid malignancy statistics by World Health Organization subtypes","volume":"66","author":"Teras","year":"2016","journal-title":"CA Cancer J. 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