{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T23:32:23Z","timestamp":1784763143229,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish ISCIII-FIS and FEDER","award":["PI15\/02156, PI15\/00067, PI18\/00591, PI19\/01384"],"award-info":[{"award-number":["PI15\/02156, PI15\/00067, PI18\/00591, PI19\/01384"]}]},{"name":"Network of Regenerative Medicine and Cellular Therapy of Castilla y Le\u00f3n","award":["."],"award-info":[{"award-number":["."]}]},{"name":"Regional Health Council of Castilla y Le\u00f3n","award":["GRS 1604\/A\/17"],"award-info":[{"award-number":["GRS 1604\/A\/17"]}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["PROYE20047GUTI"],"award-info":[{"award-number":["PROYE20047GUTI"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Regional Education Council of Junta Castilla y Le\u00f3n and European Social Fund","award":["."],"award-info":[{"award-number":["."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and\/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.<\/jats:p>","DOI":"10.3390\/cells10030559","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T21:58:07Z","timestamp":1614895087000},"page":"559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma"],"prefix":"10.3390","volume":"10","author":[{"given":"Esperanza M.","family":"Algar\u00edn","sequence":"first","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Quwaider","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1213-0457","authenticated-orcid":false,"given":"Francisco J.","family":"Campos-Laborie","sequence":"additional","affiliation":[{"name":"Bioinformatics and Functional Genomics Group, Cancer Research Center (CIC-IBMCC, CSIC\/USAL\/IBSAL), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), University of Salamanca (USAL) and Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"The Gurdon Institute (Wellcome Trust\/Cancer Research UK), University of Cambridge, Cambridge CB2 1QN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-9767","authenticated-orcid":false,"given":"Andrea","family":"D\u00edaz-Tejedor","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6108-0986","authenticated-orcid":false,"given":"Pedro","family":"Mogoll\u00f3n","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Vuelta","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Mart\u00edn-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-5935","authenticated-orcid":false,"given":"Laura","family":"San-Segundo","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Gonz\u00e1lez-M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5834-9510","authenticated-orcid":false,"given":"Norma C.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Center for Biomedical Research in Network of Cancer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4120-2787","authenticated-orcid":false,"given":"Ram\u00f3n","family":"Garc\u00eda-Sanz","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Center for Biomedical Research in Network of Cancer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-3572","authenticated-orcid":false,"given":"Teresa","family":"Pa\u00edno","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Center for Biomedical Research in Network of Cancer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-9946","authenticated-orcid":false,"given":"Javier","family":"De Las Rivas","sequence":"additional","affiliation":[{"name":"Bioinformatics and Functional Genomics Group, Cancer Research Center (CIC-IBMCC, CSIC\/USAL\/IBSAL), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), University of Salamanca (USAL) and Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-0085","authenticated-orcid":false,"given":"Enrique M.","family":"Ocio","sequence":"additional","affiliation":[{"name":"University Hospital Marqu\u00e9s de Valdecilla (IDIVAL), University of Cantabria, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2194-2841","authenticated-orcid":false,"given":"Mercedes","family":"Garayoa","sequence":"additional","affiliation":[{"name":"Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s40265-016-0573-4","article-title":"Practical Considerations for the Use of Daratumumab, a Novel CD38 Monoclonal Antibody, in Myeloma","volume":"76","author":"Moreau","year":"2016","journal-title":"Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e163","DOI":"10.1097\/HS9.0000000000000163","article-title":"Insights on Multiple Myeloma Treatment Strategies","volume":"3","author":"Mateos","year":"2018","journal-title":"Hemasphere"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nrc2189","article-title":"Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets","volume":"7","author":"Hideshima","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/CCO.0000000000000615","article-title":"The microenvironment in myeloma","volume":"32","author":"Lomas","year":"2020","journal-title":"Curr. Opin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1586\/17474086.2014.858595","article-title":"Future agents and treatment directions in multiple myeloma","volume":"7","author":"Ocio","year":"2014","journal-title":"Expert Rev. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nm.2112","article-title":"Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity","volume":"16","author":"McMillin","year":"2010","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"38927","DOI":"10.18632\/oncotarget.7792","article-title":"Extracellular vesicle cross-talk in the bone marrow microenvironment: Implications in multiple myeloma","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrd3870","article-title":"The role of tumour-stromal interactions in modifying drug response: Challenges and opportunities","volume":"12","author":"McMillin","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6504593","DOI":"10.1155\/2016\/6504593","article-title":"MicroRNAs: Novel Crossroads between Myeloma Cells and the Bone Marrow Microenvironment","volume":"2016","author":"Raimondi","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.3109\/10428194.2011.576791","article-title":"Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression","volume":"52","author":"Hao","year":"2011","journal-title":"Leuk. Lymphoma"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.3109\/10428194.2011.591004","article-title":"Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation","volume":"52","author":"Wang","year":"2011","journal-title":"Leuk. Lymphoma"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1038\/leu.2015.124","article-title":"Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo","volume":"29","author":"Morelli","year":"2015","journal-title":"Leukemia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1158\/1078-0432.CCR-15-0489","article-title":"A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells","volume":"22","author":"Gulla","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.clml.2018.06.015","article-title":"The Multiple Myeloma Drug Pipeline-2018: A Review of Small Molecules and Their Therapeutic Targets","volume":"18","author":"Abramson","year":"2018","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/bjh.14684","article-title":"Targeting anti-apoptotic BCL2 family proteins in haematological malignancies\u2014From pathogenesis to treatment","volume":"178","author":"Vogler","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1172\/JCI28281","article-title":"Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737","volume":"117","author":"Brown","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1182\/blood-2016-10-745059","article-title":"Bone marrow microenvironment\u2013derived signals induce Mcl-1 dependence in multiple myeloma","volume":"129","author":"Gupta","year":"2017","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1200\/JCO.2011.34.7898","article-title":"Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease","volume":"30","author":"Roberts","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1182\/blood-2017-06-788786","article-title":"Efficacy of venetoclax as targeted therapy for relapsed\/refractory t(11;14) multiple myeloma","volume":"130","author":"Kumar","year":"2017","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/sj.leu.2403784","article-title":"Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival","volume":"19","author":"Robillard","year":"2005","journal-title":"Leukemia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1182\/blood.V100.1.194","article-title":"Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-xL is an essential survival protein of human myeloma cells","volume":"100","author":"Derenne","year":"2002","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1182\/blood.V99.6.1885","article-title":"Myeloid cell factor-1 is a critical survival factor for multiple myeloma","volume":"99","author":"Zhang","year":"2002","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature19830","article-title":"The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models","volume":"538","author":"Kotschy","year":"2016","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1038\/s41467-018-07551-w","article-title":"Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia","volume":"9","author":"Tron","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Caenepeel, S., Brown, S.P., Belmontes, B., Moody, G., Keegan, K.S., Chui, D., Whittington, D.A., Huang, X., Poppe, L., and Cheng, A.C. (2018). AMG 176, a Selective MCL1 Inhibitor, is Effective in Hematological Cancer Models Alone and in Combination with Established Therapies. Cancer Discov., CD-18-0387.","DOI":"10.1158\/2159-8290.CD-18-0387"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Algar\u00edn, E.M., D\u00edaz-Tejedor, A., Mogoll\u00f3n, P., Hern\u00e1ndez-Garc\u00eda, S., Corchete, L.A., San-Segundo, L., Mart\u00edn-S\u00e1nchez, M., Gonz\u00e1lez-M\u00e9ndez, L., Schoumacher, M., and Banquet, S. (2019). Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma. Haematologica.","DOI":"10.3324\/haematol.2018.212308"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1038\/sj.onc.1206423","article-title":"A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells","volume":"22","author":"Jourdan","year":"2003","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1111\/febs.14505","article-title":"Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming","volume":"285","author":"Boise","year":"2018","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1158\/1078-0432.CCR-13-1657","article-title":"Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease","volume":"20","author":"Quwaider","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.3389\/fonc.2018.00645","article-title":"BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker","volume":"8","author":"Tessoulin","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/cdd.2017.183","article-title":"Why do BCL-2 inhibitors work and where should we use them in the clinic?","volume":"25","author":"Montero","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41580-018-0089-8","article-title":"Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins","volume":"20","author":"Singh","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.canlet.2011.12.021","article-title":"BH3 profiling \u2013 Measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions","volume":"332","author":"Letai","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1182\/blood-2018-03-836718","article-title":"BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment","volume":"132","author":"Maiga","year":"2018","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1038\/sj.cdd.4400758","article-title":"Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: Interleukin-6, interferon-alpha and insulin-like growth factor 1","volume":"7","author":"Jourdan","year":"2000","journal-title":"Cell Death Differ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e22008","DOI":"10.1002\/jbt.22008","article-title":"LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR-193a\/MCL1 pathway","volume":"32","author":"Wu","year":"2018","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1158\/1535-7163.MCT-10-0427","article-title":"A MicroRNA Screen to Identify Modulators of Sensitivity to BCL2 Inhibitor ABT-263 (Navitoclax)","volume":"9","author":"Lam","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4202","DOI":"10.1182\/bloodadvances.2019000702","article-title":"Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting","volume":"3","author":"Slomp","year":"2019","journal-title":"Blood Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1007\/s00125-017-4237-z","article-title":"MicroRNA 21 targets BCL2 mRNA to increase cell apoptosis in rat and human beta cells","volume":"60","author":"Sims","year":"2017","journal-title":"Diabetologia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1093\/nar\/gkp117","article-title":"Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells","volume":"37","author":"Wickramasinghe","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Liu, K., Du, J., and Ruan, L. (2017). MicroRNA-21 regulates the viability and apoptosis of diffuse large B-cell lymphoma cells by upregulating B cell lymphoma-2. Exp. Ther. Med.","DOI":"10.3892\/etm.2017.5021"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.arcmed.2011.01.006","article-title":"Bcl-2 Upregulation Induced by miR-21 Via a Direct Interaction Is Associated with Apoptosis and Chemoresistance in MIA PaCa-2 Pancreatic Cancer Cells","volume":"42","author":"Dong","year":"2011","journal-title":"Arch. Med. Res."},{"key":"ref_43","first-page":"3478","article-title":"miR-21 inhibitor suppresses proliferation and migration of nasopharyngeal carcinoma cells through down-regulation of BCL2 expression","volume":"7","author":"Li","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1182\/blood-2011-01-327197","article-title":"Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL\/Bcl-2 in Mcl-1-expressing myeloma cells","volume":"118","author":"Morales","year":"2011","journal-title":"Blood"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/559\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:32:59Z","timestamp":1760160779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cells10030559"],"URL":"https:\/\/doi.org\/10.3390\/cells10030559","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]}}}