{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T10:34:17Z","timestamp":1771670057946,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T00:00:00Z","timestamp":1641686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients.<\/jats:p>","DOI":"10.3390\/biom12010107","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Mucolipin TRPML2 Channel Enhances the Sensitivity of Multiple Myeloma Cell Lines to Ibrutinib and\/or Bortezomib Treatment"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-7064","authenticated-orcid":false,"given":"Giorgio","family":"Santoni","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Camerino, 62032 Camerino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8711-9941","authenticated-orcid":false,"given":"Consuelo","family":"Amantini","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4191-2148","authenticated-orcid":false,"given":"Federica","family":"Maggi","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy"},{"name":"Department of Molecular Medicine, Sapienza University, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-5303","authenticated-orcid":false,"given":"Oliviero","family":"Marinelli","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Camerino, 62032 Camerino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Santoni","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Hospital of Macerata, 62100 Macerata, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4614-5649","authenticated-orcid":false,"given":"Maria Beatrice","family":"Morelli","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Camerino, 62032 Camerino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1053\/j.seminoncol.2016.11.004","article-title":"Multiple Myeloma Epidemiology and Survival: A Unique Malignancy","volume":"43","author":"Kazandjian","year":"2016","journal-title":"Semin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMra1011442","article-title":"Multiple Myeloma","volume":"364","author":"Palumbo","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.1182\/blood-2011-06-358812","article-title":"Personalized Therapy in Multiple Myeloma According to Patient Age and Vulnerability: A Report of the European Myeloma Network (EMN)","volume":"118","author":"Palumbo","year":"2011","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/nyas.13038","article-title":"Multiple Myeloma in the Marrow: Pathogenesis and Treatments","volume":"1364","author":"Fairfield","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple Myeloma","volume":"397","author":"Pawlyn","year":"2021","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1038\/s41467-020-15740-9","article-title":"Timing the Initiation of Multiple Myeloma","volume":"11","author":"Rustad","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2582","DOI":"10.1056\/NEJMoa070389","article-title":"Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma","volume":"356","author":"Kyle","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17514","DOI":"10.3390\/ijms160817514","article-title":"Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine","volume":"16","author":"Simeon","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s40364-021-00297-6","article-title":"Key Regulators of Sensitivity to Immunomodulatory Drugs in Cancer Treatment","volume":"9","author":"Wang","year":"2021","journal-title":"Biomark. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ito, S. (2020). Proteasome Inhibitors for the Treatment of Multiple Myeloma. Cancers, 12.","DOI":"10.3390\/cancers12020265"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1053\/j.seminoncol.2018.01.004","article-title":"Proteasome Inhibitors: Structure and Function","volume":"44","author":"Nunes","year":"2017","journal-title":"Semin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/ajh.21310","article-title":"The Proteasome Inhibitor, Bortezomib Suppresses Primary Myeloma and Stimulates Bone Formation in Myelomatous and Nonmyelomatous Bones in Vivo","volume":"84","author":"Pennisi","year":"2009","journal-title":"Am. J. Hematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1080\/15384101.2014.998067","article-title":"Ibrutinib Inhibits BTK-Driven NF-\u039aB P65 Activity to Overcome Bortezomib-Resistance in Multiple Myeloma","volume":"14","author":"Murray","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e565","DOI":"10.1038\/bcj.2017.40","article-title":"Waldenstrom Macroglobulinemia Cells Devoid of BTKC481S or CXCR4WHIM-like Mutations Acquire Resistance to Ibrutinib through Upregulation of Bcl-2 and AKT Resulting in Vulnerability towards Venetoclax or MK2206 Treatment","volume":"7","author":"Paulus","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56858","DOI":"10.18632\/oncotarget.18096","article-title":"BTK Suppresses Myeloma Cellular Senescence through Activating AKT\/P27\/Rb Signaling","volume":"8","author":"Gu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.semcancer.2013.09.001","article-title":"B-Cell Receptor Signaling as a Driver of Lymphoma Development and Evolution","volume":"23","author":"Niemann","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.cellsig.2012.09.008","article-title":"BTK Inhibitor Ibrutinib Is Cytotoxic to Myeloma and Potently Enhances Bortezomib and Lenalidomide Activities through NF-\u039aB","volume":"25","author":"Rushworth","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71981","DOI":"10.18632\/oncotarget.18234","article-title":"Cell Lines Generated from a Chronic Lymphocytic Leukemia Mouse Model Exhibit Constitutive Btk and Akt Signaling","volume":"8","author":"Singh","year":"2017","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cellimm.2005.07.001","article-title":"Differential Expression and Molecular Characterisation of Lmo7, Myo1e, Sash1, and Mcoln2 Genes in Btk-Defective B-Cells","volume":"235","author":"Lindvall","year":"2005","journal-title":"Cell. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00424-009-0716-5","article-title":"The Tissue-Specific Expression of TRPML2 (MCOLN-2) Gene Is Influenced by the Presence of TRPML1","volume":"459","author":"Samie","year":"2009","journal-title":"Pfl\u00fcgers Arch.-Eur. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrg2703","article-title":"Origin and Evolution of the Adaptive Immune System: Genetic Events and Selective Pressures","volume":"11","author":"Flajnik","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3389\/fimmu.2020.00225","article-title":"TRPML cation channels in inflammation and immunity","volume":"11","author":"Spix","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/44076","article-title":"Commitment to the B-Lymphoid Lineage Depends on the Transcription Factor Pax5","volume":"401","author":"Nutt","year":"1999","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.gene.2014.11.003","article-title":"PAX5 Is the Transcriptional Activator of Mucolipin-2 (MCOLN2) Gene","volume":"555","author":"Valadez","year":"2015","journal-title":"Gene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1080\/15592294.2015.1078050","article-title":"Integrated Methylome and Transcriptome Analysis Reveals Novel Regulatory Elements in Pediatric Acute Lymphoblastic Leukemia","volume":"10","author":"Almamun","year":"2015","journal-title":"Epigenetics"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Santoni, G., Maggi, F., Morelli, M.B., Santoni, M., and Marinelli, O. (2019). Transient Receptor Potential Cation Channels in Cancer Therapy. Med. Sci., 7.","DOI":"10.3390\/medsci7120108"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xu, M., and Dong, X.-P. (2021). Endolysosomal TRPMLs in cancer. Biomolecules, 11.","DOI":"10.3390\/biom11010065"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2174\/187153011794982068","article-title":"TRP Channels and Cancer: New Targets for Diagnosis and Chemotherapy","volume":"11","author":"Santoni","year":"2011","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/carcin\/bgs328","article-title":"Triggering of the TRPV2 Channel by Cannabidiol Sensitizes Glioblastoma Cells to Cytotoxic Chemotherapeutic Agents","volume":"34","author":"Nabissi","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1002\/ijc.29573","article-title":"Cannabidiol Stimulates Aml-1a-Dependent Glial Differentiation and Inhibits Glioma Stem-like Cells Proliferation by Inducing Autophagy in a TRPV2-Dependent Manner","volume":"137","author":"Nabissi","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1002\/ijc.28591","article-title":"The Effects of Cannabidiol and Its Synergism with Bortezomib in Multiple Myeloma Cell Lines. A Role for Transient Receptor Potential Vanilloid Type-2","volume":"134","author":"Morelli","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43654","DOI":"10.18632\/oncotarget.9661","article-title":"Overexpression of Transient Receptor Potential Mucolipin-2 Ion Channels in Gliomas: Role in Tumor Growth and Progression","volume":"7","author":"Morelli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3322\/caac.21252","article-title":"Understanding Biology to Tackle the Disease: Multiple Myeloma from Bench to Bedside, and Back","volume":"64","author":"Bianchi","year":"2014","journal-title":"CA A Cancer J. Clin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1080\/10428194.2018.1443337","article-title":"Phase 1 Trial of Ibrutinib and Carfilzomib Combination Therapy for Relapsed or Relapsed and Refractory Multiple Myeloma","volume":"59","author":"Chari","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/ejh.13377","article-title":"A Phase 2 Study of Ibrutinib in Combination with Bortezomib and Dexamethasone in Patients with Relapsed\/Refractory Multiple Myeloma","volume":"104","author":"Hajek","year":"2020","journal-title":"Eur. J. Haematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/hon.2723","article-title":"Final Analysis of a Phase 1\/2b Study of Ibrutinib Combined with Carfilzomib\/Dexamethasone in Patients with Relapsed\/Refractory Multiple Myeloma","volume":"38","author":"Chari","year":"2020","journal-title":"Hematol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"69961","DOI":"10.18632\/oncotarget.11572","article-title":"Preclinical Investigation of Ibrutinib, a Bruton\u2019s Kinase Tyrosine (Btk) Inhibitor, in Suppressing Glioma Tumorigenesis and Stem Cell Phenotypes","volume":"7","author":"Wei","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fnmol.2019.00002","article-title":"Specific Expression of a New Bruton Tyrosine Kinase Isoform (P65BTK) in the Glioblastoma Gemistocytic Histotype","volume":"12","author":"Sala","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13046-017-0600-7","article-title":"High Expression of Bruton\u2019s Tyrosine Kinase (BTK) Is Required for EGFR-Induced NF-\u039aB Activation and Predicts Poor Prognosis in Human Glioma","volume":"36","author":"Yue","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s13046-017-0549-6","article-title":"Ibrutinib, a Bruton\u2019s Tyrosine Kinase Inhibitor, Exhibits Antitumoral Activity and Induces Autophagy in Glioblastoma","volume":"36","author":"Wang","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/1\/107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:01:48Z","timestamp":1760364108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/1\/107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,9]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["biom12010107"],"URL":"https:\/\/doi.org\/10.3390\/biom12010107","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,9]]}}}