{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:21:56Z","timestamp":1787026916485,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Mantle Cell Lymphoma (MCL) is still an incurable B-cell malignancy characterized by poor prognosis and frequent relapses. B Cell Receptor (BCR) signaling inhibitors, in particular of the kinases BTK and PI3K\u03b3\/\u03b4, have demonstrated clinically meaningful anti-proliferative effects in B cell tumors. However, refractoriness to these drugs may develop, portending a dismal prognosis. Protein kinase CK1\u03b1 is an emerging pro-growth enzyme in B cell malignancies. In multiple myeloma, this kinase sustains \u03b2-catenin and AKT-dependent survival and is involved in the activation of NF-\u03baB in B cells. In this study, we analyzed the role of CK1\u03b1 on MCL cell survival and proliferation, on the regulation of BCR-related BTK, NF-\u03baB, PI3K\/AKT signaling cascades and the effects of CK1\u03b1 chemical inhibition or gene silencing in association with the BTK inhibitor Ibrutinib or the PI3K\u03b3\/\u03b4 inhibitor Duvelisib. CK1\u03b1 was found highly expressed in MCL cells as compared to normal B cells. The inactivation\/loss of CK1\u03b1 caused MCL cell apoptosis and proliferation arrest. CK1\u03b1 sustained BCR signaling, in particular the NF-\u03baB, AKT and BTK pathways by modulating the phosphorylation of Ser 652 on CARD11, Ser 536 p65 on NF-\u03baB, Ser 473 on AKT, Tyr 223 on BTK, as well as the protein levels. We also provided evidence that CK1\u03b1-mediated regulation of CARD11 and BTK likely implicates a physical interaction. The combination of CK1\u03b1 inhibition with Ibrutinib or Duvelisib synergistically increased cytotoxicity, leading to a further decrease of the activation of BCR signaling pathways. Therefore, CK1\u03b1 sustains MCL growth through the regulation of BCR-linked survival signaling cascades and protects from Ibrutinib\/Duvelisib-induced apoptosis. Thus, CK1\u03b1 could be considered as a rational molecular target for the treatment of MCL, in association with novel agents.<\/jats:p>","DOI":"10.3389\/fonc.2021.733848","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T01:03:18Z","timestamp":1634173398000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Protein Kinase CK1\u03b1 Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma"],"prefix":"10.3389","volume":"11","author":[{"given":"Sabrina","family":"Manni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fregnani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Quotti 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