{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:52:49Z","timestamp":1793641969235,"version":"4.5.1"},"reference-count":182,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007833","name":"Hamad Medical Corporation","doi-asserted-by":"publisher","award":["MRC-01-18-120"],"award-info":[{"award-number":["MRC-01-18-120"]}],"id":[{"id":"10.13039\/100007833","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host\u2019s immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-\u03ba\u03b2, PI3K\/AKT and JAK\/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.<\/jats:p>","DOI":"10.3390\/ijms21145002","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T10:35:18Z","timestamp":1594809318000},"page":"5002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma"],"prefix":"10.3390","volume":"21","author":[{"given":"Sabah","family":"Akhtar","sequence":"first","affiliation":[{"name":"Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayyiba A.","family":"Ali","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammara","family":"Faiyaz","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar S.","family":"Khan","sequence":"additional","affiliation":[{"name":"Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6147-9399","authenticated-orcid":false,"given":"Syed Shadab","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow 226003, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kulinski","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halima El","family":"Omri","sequence":"additional","affiliation":[{"name":"National Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3640-6275","authenticated-orcid":false,"given":"Ajaz A.","family":"Bhat","sequence":"additional","affiliation":[{"name":"Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-6710","authenticated-orcid":false,"given":"Shahab","family":"Uddin","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar"},{"name":"Dermatology Institute, Department of Dermatology and Venereology, Hamad Medical Corporation, Doha 3050, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1136\/jclinpath-2015-203414","article-title":"Molecular mechanisms in multiple myeloma drug resistance","volume":"69","author":"Nikesitch","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Roy, P., Sarkar, U.A., and Basak, S. (2018). The NF-kappaB Activating Pathways in Multiple Myeloma. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020059"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1001\/jamaoncol.2018.2128","article-title":"Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"4","author":"Cowan","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Baek, S.H., Lee, J.H., Kim, C., Ko, J.H., Ryu, S.H., Lee, S.G., Yang, W.M., Um, J.Y., Chinnathambi, A., and Alharbi, S.A. (2017). Ginkgolic Acid C 17:1, Derived from Ginkgo biloba Leaves, Suppresses Constitutive and Inducible STAT3 Activation through Induction of PTEN and SHP-1 Tyrosine Phosphatase. Molecules, 22.","DOI":"10.3390\/molecules22020276"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s12032-009-9403-9","article-title":"A survey of prognostic value of serum factors in multiple myeloma patients before treatment: Macrophage-colony stimulating factor (M-CSF) is a powerful predictor of survival","volume":"28","author":"Kowalska","year":"2011","journal-title":"Med. Oncol."},{"key":"ref_6","first-page":"1010","article-title":"Monitoring Disease Status in Multiple Myeloma in View of Proliferation-leading Cytokines","volume":"2","year":"2017","journal-title":"J. Hematol. Mult. Myeloma"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zheng, M.M., Zhang, Z., Bemis, K., Belch, A.R., Pilarski, L.M., Shively, J.E., and Kirshner, J. (2013). The systemic cytokine environment is permanently altered in multiple myeloma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058504"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1046\/j.1365-2249.2001.01582.x","article-title":"Deregulated cytokine network and defective Th1 immune response in multiple myeloma","volume":"125","author":"Frassanito","year":"2001","journal-title":"Clin. Exp. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1182\/blood.V95.2.610","article-title":"Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma","volume":"95","author":"Tinhofer","year":"2000","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1852517","DOI":"10.1155\/2017\/1852517","article-title":"Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma","volume":"2017","author":"Musolino","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.exphem.2010.06.012","article-title":"The cytokine\/chemokine pattern in the bone marrow environment of multiple myeloma patients","volume":"38","author":"Cao","year":"2010","journal-title":"Exp. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1182\/blood-2003-06-1992","article-title":"IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells","volume":"103","author":"Lee","year":"2004","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1365-2141.2005.05443.x","article-title":"Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells","volume":"129","author":"Pellegrino","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1182\/blood.V98.2.428","article-title":"Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration","volume":"98","author":"Podar","year":"2001","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000046612","article-title":"Bone marrow angiogenesis and plasma cell angiogenic and invasive potential in patients with active multiple myeloma","volume":"106","author":"Vacca","year":"2001","journal-title":"Acta Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dewald, J.H., Colomb, F., Bobowski-Gerard, M., Groux-Degroote, S., and Delannoy, P. (2016). Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer. Cells, 5.","DOI":"10.3390\/cells5040043"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1586\/erm.10.31","article-title":"Bone marrow microenvironment in myelomagenesis: Its potential role in early diagnosis","volume":"10","author":"Balakumaran","year":"2010","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Roesch, S., Rapp, C., Dettling, S., and Herold-Mende, C. (2018). When Immune Cells Turn Bad-Tumor-Associated Microglia\/Macrophages in Glioma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020436"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yahfoufi, N., Alsadi, N., Jambi, M., and Matar, C. (2018). The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients, 10.","DOI":"10.3390\/nu10111618"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"788","DOI":"10.3389\/fendo.2018.00788","article-title":"Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma","volume":"9","author":"Harmer","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1038\/sj.leu.2403084","article-title":"Expression of VEGF and its receptors by myeloma cells","volume":"17","author":"Kumar","year":"2003","journal-title":"Leukemia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/sj.bjc.6601613","article-title":"Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: Study in the 5T33MM model","volume":"90","author":"Menu","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"157496","DOI":"10.1155\/2012\/157496","article-title":"Bone marrow microenvironment in multiple myeloma progression","volume":"2012","author":"Manier","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1182\/blood-2004-01-0037","article-title":"Advances in biology of multiple myeloma: Clinical applications","volume":"104","author":"Hideshima","year":"2004","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"El Arfani, C., De Veirman, K., Maes, K., De Bruyne, E., and Menu, E. (2018). Metabolic Features of Multiple Myeloma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041200"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.3389\/fimmu.2018.02204","article-title":"Checkpoint Inhibition in Myeloma: Opportunities and Challenges","volume":"9","author":"Costa","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev-immunol-031210-101324","article-title":"Natural innate and adaptive immunity to cancer","volume":"29","author":"Vesely","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s12307-011-0086-3","article-title":"The immune microenvironment of myeloma","volume":"4","author":"Noonan","year":"2011","journal-title":"Cancer Microenviron."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2040620718822660","DOI":"10.1177\/2040620718822660","article-title":"Immunotherapy in myeloma: How far have we come?","volume":"10","author":"Franssen","year":"2019","journal-title":"Ther. Adv. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5262","DOI":"10.1158\/1078-0432.CCR-07-1157","article-title":"Transforming growth factor-beta and the immune response: Implications for anticancer therapy","volume":"13","author":"Wrzesinski","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1182\/blood-2016-01-691162","article-title":"APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment","volume":"127","author":"Tai","year":"2016","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41375-018-0242-6","article-title":"APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: Therapeutic implications","volume":"33","author":"Tai","year":"2019","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13045-018-0582-8","article-title":"Next generation of immune checkpoint therapy in cancer: New developments and challenges","volume":"11","author":"Dholaria","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e321","DOI":"10.1038\/bcj.2015.49","article-title":"The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies","volume":"5","author":"Dosani","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/j.1699-0463.1991.tb05159.x","article-title":"Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors","volume":"99","author":"Nielsen","year":"1991","journal-title":"APMIS"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1007\/s00018-016-2135-z","article-title":"Immune responses in multiple myeloma: Role of the natural immune surveillance and potential of immunotherapies","volume":"73","author":"Guillerey","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e285","DOI":"10.1038\/bcj.2015.7","article-title":"Immunomodulatory molecule PD-L1 is expressed on malignant plasma cells and myeloma-propagating pre-plasma cells in the bone marrow of multiple myeloma patients","volume":"5","author":"Yousef","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/imr.12233","article-title":"Targeting the bone marrow microenvironment in multiple myeloma","volume":"263","author":"Kawano","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_42","first-page":"409","article-title":"PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell\/myeloma fusion vaccine","volume":"34","author":"Rosenblatt","year":"2011","journal-title":"J. Immunother. (Hagerstown Md 1997)"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1182\/blood-2006-10-051482","article-title":"Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-(1) and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway","volume":"110","author":"Liu","year":"2007","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13045-018-0589-1","article-title":"Modulating PD-L1 expression in multiple myeloma: An alternative strategy to target the PD-1\/PD-L1 pathway","volume":"11","author":"Rastgoo","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1182\/asheducation-2016.1.528","article-title":"Checkpoint inhibition in myeloma","volume":"1","author":"Benson","year":"2016","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1158\/2326-6066.CIR-15-0296","article-title":"Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 (PD-L1) to PD-1","volume":"4","author":"Ishibashi","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/leu.2012.213","article-title":"Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma","volume":"27","author":"Tamura","year":"2013","journal-title":"Leukemia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1182\/blood-2010-02-271874","article-title":"The PD-1\/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: A therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody","volume":"116","author":"Benson","year":"2010","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1182\/blood-2016-08-731885","article-title":"Targeting the PD-1\/PD-L1 axis in multiple myeloma: A dream or a reality?","volume":"129","author":"Rosenblatt","year":"2017","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.3389\/fimmu.2018.02749","article-title":"Promises and Pitfalls in the Use of PD-1\/PD-L1 Inhibitors in Multiple Myeloma","volume":"9","author":"Oliva","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1038\/leu.2016.84","article-title":"Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade","volume":"30","author":"Suen","year":"2016","journal-title":"Leukemia"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1172\/JCI82646","article-title":"Immunosurveillance and therapy of multiple myeloma are CD226 dependent","volume":"125","author":"Guillerey","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/471561a","article-title":"Melanoma drug wins US approval","volume":"471","author":"Ledford","year":"2011","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1634\/theoncologist.13-S4-2","article-title":"The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation","volume":"13","author":"Wolchok","year":"2008","journal-title":"Oncologist"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/35105024","article-title":"T-cell regulation by CD28 and CTLA-4","volume":"1","author":"Alegre","year":"2001","journal-title":"Nat. Rev. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1600-065X.2009.00770.x","article-title":"CD28 and CTLA-4 coreceptor expression and signal transduction","volume":"229","author":"Rudd","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6154","DOI":"10.7150\/jca.31752","article-title":"Potential Therapeutic Roles of Exosomes in Multiple Myeloma: A Systematic Review","volume":"10","author":"Li","year":"2019","journal-title":"J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"665","DOI":"10.3892\/or.2017.5714","article-title":"Exosomes: New players in cancer (Review)","volume":"38","author":"Guo","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1182\/blood-2016-09-742296","article-title":"Prognostic role of circulating exosomal miRNAs in multiple myeloma","volume":"129","author":"Manier","year":"2017","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15004","DOI":"10.1038\/sigtrans.2015.4","article-title":"The role of MicroRNAs in human cancer","volume":"1","author":"Peng","year":"2016","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1182\/blood-2009-01-198408","article-title":"MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma","volume":"113","author":"Roccaro","year":"2009","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"521586","DOI":"10.1155\/2014\/521586","article-title":"MicroRNA: Important player in the pathobiology of multiple myeloma","volume":"2014","author":"Bi","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Handa, H., Murakami, Y., Ishihara, R., Kimura-Masuda, K., and Masuda, Y. (2019). The Role and Function of microRNA in the Pathogenesis of Multiple Myeloma. Cancers (Basel), 11.","DOI":"10.3390\/cancers11111738"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Butova, R., Vychytilova-Faltejskova, P., Souckova, A., Sevcikova, S., and Hajek, R. (2019). Long Non-Coding RNAs in Multiple Myeloma. Noncoding RNA, 5.","DOI":"10.3390\/ncrna5010013"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4465","DOI":"10.2147\/OTT.S143612","article-title":"Oncogenic role of microRNA-20a in human multiple myeloma","volume":"10","author":"Wang","year":"2017","journal-title":"Onco. Targets Ther."},{"key":"ref_66","first-page":"10001","article-title":"Effects of microRNA-20a on the proliferation, migration and apoptosis of multiple myeloma via the PTEN\/PI3K\/AKT signaling pathway","volume":"15","author":"Jiang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1182\/blood-2007-03-081133","article-title":"Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer","volume":"110","author":"Loffler","year":"2007","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1158\/1078-0432.CCR-12-3325","article-title":"Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth","volume":"19","author":"Leone","year":"2013","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1101\/sqb.2008.73.035","article-title":"Wnt signaling and stem cell control","volume":"73","author":"Nusse","year":"2008","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-018-0615-3","article-title":"Wnt signaling in multiple myeloma: A central player in disease with therapeutic potential","volume":"11","author":"Spaan","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrm3470","article-title":"The complex world of WNT receptor signalling","volume":"13","author":"Niehrs","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/s41375-019-0404-1","article-title":"Aberrant Wnt signaling in multiple myeloma: Molecular mechanisms and targeting options","volume":"33","author":"Kocemba","year":"2019","journal-title":"Leukemia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e207","DOI":"10.1038\/bcj.2014.29","article-title":"The role of epigenetics in the biology of multiple myeloma","volume":"4","author":"Dimopoulos","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrc2389","article-title":"Wnt signalling and its impact on development and cancer","volume":"8","author":"Klaus","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/carcin\/bgs333","article-title":"miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF","volume":"34","author":"Sun","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nature06100","article-title":"MicroRNA control of Nodal signalling","volume":"449","author":"Martello","year":"2007","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Li, H., Zhang, Z., Bi, Y., Yang, D., Zhang, L., and Liu, J. (2014). Expression characteristics of beta-catenin in scallop Chlamys farreri gonads and its role as a potential upstream gene of Dax1 through canonical Wnt signalling pathway regulating the spermatogenesis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115917"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1158\/1078-0432.CCR-11-2212","article-title":"Multiple myeloma mesenchymal stem cells: Characterization, origin, and tumor-promoting effects","volume":"18","author":"Reagan","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/blood-2008-11-191577","article-title":"Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma","volume":"114","author":"Fulciniti","year":"2009","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1634\/stemcells.2005-0220","article-title":"A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: A potential role in the development of lytic bone disease and tumor progression in multiple myeloma","volume":"24","author":"Gunn","year":"2006","journal-title":"Stem Cells"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.ijrobp.2015.04.007","article-title":"MiR-20a Induces Cell Radioresistance by Activating the PTEN\/PI3K\/Akt Signaling Pathway in Hepatocellular Carcinoma","volume":"92","author":"Zhang","year":"2015","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Yang, Z., Fang, S., Di, Y., Ying, W., Tan, Y., and Gu, W. (2015). Modulation of NF-kappaB\/miR-21\/PTEN pathway sensitizes non-small cell lung cancer to cisplatin. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121547"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.exphem.2015.04.010","article-title":"Novel therapeutic strategies for multiple myeloma","volume":"43","author":"Mimura","year":"2015","journal-title":"Exp. Hematol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Sanchez, V.E., Nichols, C., Kim, H.N., Gang, E.J., and Kim, Y.M. (2019). Targeting PI3K Signaling in Acute Lymphoblastic Leukemia. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020412"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"14040","DOI":"10.1074\/jbc.M108975200","article-title":"The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria","volume":"277","author":"Tsuruta","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3389\/fonc.2014.00252","article-title":"The PTEN\/PI3K\/AKT Pathway in vivo, Cancer Mouse Models","volume":"4","author":"Carnero","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4458","DOI":"10.1158\/0008-5472.CAN-13-3652","article-title":"Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition","volume":"74","author":"Mimura","year":"2014","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1182\/blood-2017-07-797050","article-title":"Syndecan-1 promotes Wnt\/beta-catenin signaling in multiple myeloma by presenting Wnts and R-spondins","volume":"131","author":"Ren","year":"2018","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Gao, L., Chen, B., Li, J., Yang, F., Cen, X., Liao, Z., and Long, X. (2017). Wnt\/beta-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181346"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.leukres.2017.07.001","article-title":"Anti-proliferative activity of CGK012 against multiple myeloma cells via Wnt\/beta-catenin signaling attenuation","volume":"60","author":"Choi","year":"2017","journal-title":"Leuk Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1158\/1535-7163.MCT-16-0624","article-title":"beta-Catenin Inhibitor BC2059 Is Efficacious as Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma","volume":"16","author":"Savvidou","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1080\/10428194.2017.1421760","article-title":"PI3K\/AKT\/mTOR pathway in multiple myeloma: From basic biology to clinical promise","volume":"59","author":"Ramakrishnan","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"61093","DOI":"10.18632\/oncotarget.17862","article-title":"Endoplasmic reticulum stress induces autophagy and apoptosis while inhibiting proliferation and drug resistance in multiple myeloma through the PI3K\/Akt\/mTOR signaling pathway","volume":"8","author":"Fu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4280","DOI":"10.1074\/jbc.M116.733030","article-title":"Autocrine and Paracrine Interactions between Multiple Myeloma Cells and Bone Marrow Stromal Cells by Growth Arrest-specific Gene 6 Cross-talk with Interleukin-6","volume":"292","author":"Furukawa","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.3892\/ol.2016.5048","article-title":"Plumbagin inhibits cell proliferation and promotes apoptosis in multiple myeloma cells through inhibition of the PI3K\/Akt-mTOR pathway","volume":"12","author":"Wu","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/ejh.12436","article-title":"The effect of the dual PI3K and mTOR inhibitor BEZ235 on tumour growth and osteolytic bone disease in multiple myeloma","volume":"94","author":"Gan","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2217\/14796694.3.6.639","article-title":"PI3 kinase\/AKT pathway as a therapeutic target in multiple myeloma","volume":"3","author":"Harvey","year":"2007","journal-title":"Future Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6972","DOI":"10.1002\/jcb.27879","article-title":"Heme oxygenase-1 attenuates the inhibitory effect of bortezomib against the APRIL-NF-kappaB-CCL3 signaling pathways in multiple myeloma cells: Corelated with bortezomib tolerance in multiple myeloma","volume":"120","author":"He","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/MOH.0b013e328302c7f4","article-title":"NF-kappaB in the pathogenesis and treatment of multiple myeloma","volume":"15","author":"Li","year":"2008","journal-title":"Curr. Opin. Hematol."},{"key":"ref_100","first-page":"285","article-title":"The short-term effect of histone deacetylase inhibitors, chidamide and valproic acid, on the NFkappaB pathway in multiple myeloma cells","volume":"43","author":"Liu","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/1476-4598-9-176","article-title":"Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells","volume":"9","author":"Markovina","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1046\/j.1365-2141.2001.03102.x","article-title":"Analysis of expression of nuclear factor kappa B (NF-kappa B) in multiple myeloma: Downregulation of NF-kappa B induces apoptosis","volume":"115","author":"Ni","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Ni, H., Zhao, W., Kong, X., Li, H., and Ouyang, J. (2014). NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095846"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.canlet.2017.06.016","article-title":"Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK\/STAT pathway inhibition in myeloma patients","volume":"403","author":"Eugenio","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12964-017-0177-y","article-title":"The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells","volume":"15","author":"Seif","year":"2017","journal-title":"Cell Commun. Signal."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Beldi-Ferchiou, A., Skouri, N., Ben Ali, C., Safra, I., Abdelkefi, A., Ladeb, S., Mrad, K., Ben Othman, T., and Ben Ahmed, M. (2017). Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK\/STAT3 pathway and the progression of the disease in multiple myeloma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174835"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ejphar.2013.02.002","article-title":"Bortezomib influences the expression of malignant plasma cells membrane antigens","volume":"706","author":"Tagoug","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/leu.2008.259","article-title":"Bone marrow microenvironment and the identification of new targets for myeloma therapy","volume":"23","author":"Podar","year":"2009","journal-title":"Leukemia"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"671","DOI":"10.2174\/156800906779010227","article-title":"The JAK-STAT pathway: A therapeutic target in hematological malignancies","volume":"6","author":"Ferrajoli","year":"2006","journal-title":"Curr. Cancer Drug Targets."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1080\/13543776.2017.1339688","article-title":"MEK inhibitors in oncology: A patent review (2015-Present)","volume":"27","author":"Mahapatra","year":"2017","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e337","DOI":"10.1038\/oncsis.2017.36","article-title":"Molecular signaling in multiple myeloma: Association of RAS\/RAF mutations and MEK\/ERK pathway activation","volume":"6","author":"Xu","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1038\/bcj.2013.1","article-title":"MEK inhibitors as a chemotherapeutic intervention in multiple myeloma","volume":"3","author":"Gerondakis","year":"2013","journal-title":"Blood Cancer J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1038\/onc.2009.403","article-title":"Sorafenib, a dual Raf kinase\/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs","volume":"29","author":"Ramakrishnan","year":"2010","journal-title":"Oncogene"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/j.1471-4159.2009.06475.x","article-title":"Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K\/Akt and\/or MEK\/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine","volume":"112","author":"Laing","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_115","first-page":"76","article-title":"Multiple myeloma and bone disease: Pathogenesis and current therapeutic approaches","volume":"14","author":"Papadopoulou","year":"2010","journal-title":"Hippokratia"},{"key":"ref_116","first-page":"471","article-title":"The role of RANK\/RANKL and OPG in multiple myeloma","volume":"60","author":"Zdzisinska","year":"2006","journal-title":"Postepy Hig. Med. Dosw. (Online)"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/2050-7771-1-5","article-title":"Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application","volume":"1","author":"Furqan","year":"2013","journal-title":"Biomark Res."},{"key":"ref_118","first-page":"61","article-title":"Signaling via JAK tyrosine kinases: Growth hormone receptor as a model system","volume":"53","author":"Smit","year":"1998","journal-title":"Recent Prog. Horm. Res."},{"key":"ref_119","first-page":"50","article-title":"Neonatal nursing education","volume":"34","author":"Telfer","year":"1977","journal-title":"Aust. Nurses J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1182\/blood-2003-06-2151","article-title":"Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis","volume":"103","author":"Bharti","year":"2004","journal-title":"Blood"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1074-7613(00)80011-4","article-title":"Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells","volume":"10","author":"Landowski","year":"1999","journal-title":"Immunity"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1038\/sj.leu.2403970","article-title":"Growth factors and antiapoptotic signaling pathways in multiple myeloma","volume":"19","author":"Lokhorst","year":"2005","journal-title":"Leukemia"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nri2093","article-title":"SOCS proteins, cytokine signalling and immune regulation","volume":"7","author":"Yoshimura","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/43213","article-title":"A new protein containing an SH2 domain that inhibits JAK kinases","volume":"387","author":"Endo","year":"1997","journal-title":"Nature"},{"key":"ref_125","first-page":"e24053","article-title":"SOCS, inflammation, and cancer","volume":"2","author":"Kondo","year":"2013","journal-title":"JAKSTAT"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1182\/blood-2009-06-225839","article-title":"Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities","volume":"114","author":"Mottok","year":"2009","journal-title":"Blood"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1002\/ijc.27318","article-title":"Role of SOCS1 in tumor progression and therapeutic application","volume":"130","author":"Zhang","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1517\/14712598.6.3.231","article-title":"STAT3 as a therapeutic target in head and neck cancer","volume":"6","author":"Leeman","year":"2006","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1189\/jlb.0410217","article-title":"gp130 at the nexus of inflammation, autoimmunity, and cancer","volume":"88","author":"Silver","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.ctrv.2012.04.007","article-title":"Interleukin-6 signaling pathway in targeted therapy for cancer","volume":"38","author":"Guo","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nri1995","article-title":"Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment","volume":"7","author":"Yu","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00018-012-1145-8","article-title":"Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells","volume":"70","author":"Parrillas","year":"2013","journal-title":"Cell Mol. Life Sci."},{"key":"ref_133","first-page":"1221","article-title":"Friend or foe: Emerging role of nuclear factor kappa-light-chain-enhancer of activated B cells in cell senescence","volume":"6","author":"Mowla","year":"2013","journal-title":"Onco. Targets Ther."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-kappaB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-kappaB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell Res."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Imbert, V., and Peyron, J.F. (2017). NF-kappaB in Hematological Malignancies. Biomedicines, 5.","DOI":"10.3390\/biomedicines5020027"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1158\/2326-6066.CIR-14-0112","article-title":"NF-kappaB, an active player in human cancers","volume":"2","author":"Xia","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri.2017.52","article-title":"The non-canonical NF-kappaB pathway in immunity and inflammation","volume":"17","author":"Sun","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/embr.201337983","article-title":"The IkappaB kinase complex in NF-kappaB regulation and beyond","volume":"15","author":"Hinz","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1476-4598-12-86","article-title":"The complexity of NF-kappaB signaling in inflammation and cancer","volume":"12","author":"Hoesel","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"59","DOI":"10.18632\/oncotarget.109","article-title":"A critical role for the NFkB pathway in multiple myeloma","volume":"1","author":"Demchenko","year":"2010","journal-title":"Oncotarget"},{"key":"ref_143","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_144","doi-asserted-by":"crossref","first-page":"4614","DOI":"10.1182\/blood-2008-07-170464","article-title":"The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor","volume":"113","author":"Sprynski","year":"2009","journal-title":"Blood"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1038\/sj.onc.1205664","article-title":"Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1\/Akt signaling in human multiple myeloma cells: Therapeutic implications","volume":"21","author":"Mitsiades","year":"2002","journal-title":"Oncogene"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"E1237","DOI":"10.1111\/j.1464-410X.2012.11569.x","article-title":"A comprehensive immunohistochemical and molecular approach to the PI3K\/AKT\/mTOR (phosphoinositide 3-kinase\/v-akt murine thymoma viral oncogene\/mammalian target of rapamycin) pathway in bladder urothelial carcinoma","volume":"110","author":"Korkolopoulou","year":"2012","journal-title":"BJU Int."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.blre.2018.11.003","article-title":"The impact of NF-kappaB signaling on pathogenesis and current treatment strategies in multiple myeloma","volume":"34","author":"Vrabel","year":"2019","journal-title":"Blood Rev."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Gu, C., Jing, X., Holman, C., Sompallae, R., Zhan, F., Tricot, G., Yang, Y., and Janz, S. (2018). Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-5015-0"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.bbagrm.2011.09.004","article-title":"FOXM1: From cancer initiation to progression and treatment","volume":"1819","author":"Koo","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/1479-5876-10-200","article-title":"Overexpression of FoxM1 is associated with tumor progression in patients with clear cell renal cell carcinoma","volume":"10","author":"Xue","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1182\/blood-2012-01-405985","article-title":"Clonal competition with alternating dominance in multiple myeloma","volume":"120","author":"Keats","year":"2012","journal-title":"Blood"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/leu.2014.341","article-title":"PTPROt-mediated regulation of p53\/Foxm1 suppresses leukemic phenotype in a CLL mouse model","volume":"29","author":"Motiwala","year":"2015","journal-title":"Leukemia"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"6471","DOI":"10.1038\/ncomms7471","article-title":"Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia","volume":"6","author":"Buchner","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1158\/0008-5472.CAN-15-0828","article-title":"Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression","volume":"76","author":"Bisikirska","year":"2016","journal-title":"Cancer Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3324\/haematol.2011.053421","article-title":"Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma","volume":"97","author":"Uddin","year":"2012","journal-title":"Haematologica"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41408-018-0060-0","article-title":"Upregulation of FOXM1 in a subset of relapsed myeloma results in poor outcome","volume":"8","author":"Gu","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/leu.2015.334","article-title":"FOXM1 is a therapeutic target for high-risk multiple myeloma","volume":"30","author":"Gu","year":"2016","journal-title":"Leukemia"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1182\/blood-2014-05-573741","article-title":"Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma","volume":"125","author":"Kumar","year":"2015","journal-title":"Blood"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.1158\/0008-5472.CAN-07-6404","article-title":"A novel therapeutic combination using PD 0332991 and bortezomib: Study in the 5T33MM myeloma model","volume":"68","author":"Menu","year":"2008","journal-title":"Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2741\/4212","article-title":"Nek2 and Plk4: Prognostic markers, drivers of breast tumorigenesis and drug resistance","volume":"19","author":"Marina","year":"2014","journal-title":"Front. Biosci. (Landmark Ed)"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ccr.2012.12.001","article-title":"NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers","volume":"23","author":"Zhou","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1039\/C4OB02238F","article-title":"Expanding the scope of fused pyrimidines as kinase inhibitor scaffolds: Synthesis and modification of pyrido[3,4-d]pyrimidines","volume":"13","author":"Innocenti","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"23","DOI":"10.7314\/APJCP.2015.16.1.23","article-title":"FoxM1 as a novel therapeutic target for cancer drug therapy","volume":"16","author":"Xu","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1158\/1541-7786.MCR-09-0432","article-title":"FOXM1 confers acquired cisplatin resistance in breast cancer cells","volume":"8","author":"Kwok","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.4161\/cc.10.24.18544","article-title":"Thiostrepton, proteasome inhibitors and FOXM1","volume":"10","author":"Gartel","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"17466","DOI":"10.18632\/oncotarget.24739","article-title":"FoxM1 is an independent poor prognostic marker and therapeutic target for advanced Middle Eastern breast cancer","volume":"9","author":"Siraj","year":"2018","journal-title":"Oncotarget"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"8010","DOI":"10.1200\/JCO.2018.36.15_suppl.8010","article-title":"A phase 3 randomized study of pembrolizumab (pembro) plus lenalidomide (len) and low-dose dexamethasone (Rd) versus Rd for newly diagnosed and treatment-naive multiple myeloma (MM): KEYNOTE-185","volume":"36","author":"Usmani","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1200\/JCO.2018.36.15_suppl.8021","article-title":"A phase 3 randomized study of pembrolizumab (Pembro) plus pomalidomide (Pom) and dexamethasone (Dex) for relapsed\/refractory multiple myeloma (RRMM): KEYNOTE-183","volume":"36","author":"Mateos","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1056\/NEJMoa1516282","article-title":"Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"374","author":"Moreau","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s12185-019-02607-z","article-title":"Thalidomide maintenance therapy in Japanese myeloma patients: A multicenter, phase II clinical trial (COMET study)","volume":"109","author":"Murakami","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.critrevonc.2013.05.012","article-title":"Role of thalidomide in the treatment of patients with multiple myeloma","volume":"88","author":"Morgan","year":"2013","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.2217\/fon-2017-0616","article-title":"Isatuximab plus pomalidomide\/dexamethasone versus pomalidomide\/dexamethasone in relapsed\/refractory multiple myeloma: ICARIA Phase III study design","volume":"14","author":"Richardson","year":"2018","journal-title":"Future Oncol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1016\/S0140-6736(19)32556-5","article-title":"Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study","volume":"394","author":"Attal","year":"2019","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.1158\/1078-0432.CCR-18-2752","article-title":"Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38\/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release","volume":"25","author":"Fajardo","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s12185-019-02648-4","article-title":"Evaluation of the safety and efficacy of daratumumab outside of clinical trials","volume":"109","author":"Kobayashi","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4149\/neo_2018_180824N644","article-title":"Lenalidomide and dexamethasone in treatment of patients with relapsed and refractory multiple myeloma\u2014Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies","volume":"66","author":"Maisnar","year":"2019","journal-title":"Neoplasma"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.leukres.2018.03.008","article-title":"Lenalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of a non-interventional study and comparison with the pivotal phase 3 clinical trials","volume":"68","author":"Knauf","year":"2018","journal-title":"Leuk Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00432-018-2807-1","article-title":"Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy","volume":"145","author":"Danhof","year":"2019","journal-title":"J Cancer Res. Clin. Oncol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.3324\/haematol.2018.208272","article-title":"Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: A pooled analysis of two phase 1\/2 studies","volume":"104","author":"Bringhen","year":"2019","journal-title":"Haematologica"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"2040620718816699","DOI":"10.1177\/2040620718816699","article-title":"A real-world comparative analysis of carfilzomib and other systemic multiple myeloma chemotherapies in a US community oncology setting","volume":"10","author":"Rifkin","year":"2019","journal-title":"Ther. Adv. Hematol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"8574","DOI":"10.1200\/jco.2015.33.15_suppl.8574","article-title":"A phase I\/IIa study of the human anti-CD38 antibody MOR202 (MOR03087) in relapsed or refractory multiple myeloma (rrMM)","volume":"33","author":"Raab","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1182\/blood-2013-07-517276","article-title":"A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed\/refractory myeloma","volume":"123","author":"Richardson","year":"2014","journal-title":"Blood"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:50Z","timestamp":1760176130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,15]]},"references-count":182,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21145002"],"URL":"https:\/\/doi.org\/10.3390\/ijms21145002","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,15]]}}}