{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:09:11Z","timestamp":1792238951171,"version":"4.4.0"},"reference-count":23,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS"},{"name":"International Myeloma Foundation Japan"},{"name":"Japan Leukemia Foundation"},{"name":"Kanehara Foundation"},{"name":"Yokoyama Foundation"},{"name":"Japan Myeloma Society"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD.<\/jats:p>","DOI":"10.3390\/cells14070474","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment"],"prefix":"10.3390","volume":"14","author":[{"given":"Naoki","family":"Osada","sequence":"first","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8791-3263","authenticated-orcid":false,"given":"Jiro","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sae","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-6855","authenticated-orcid":false,"given":"Hiroshi","family":"Yasui","sequence":"additional","affiliation":[{"name":"Department of Hematology & Oncology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan"},{"name":"Department of Hematology\/Oncology, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3780-2993","authenticated-orcid":false,"given":"Sho","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-3787","authenticated-orcid":false,"given":"Naoto","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7249-6418","authenticated-orcid":false,"given":"Yusuke","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"},{"name":"Center for Medical Education, Teikyo University of Science, Tokyo 120-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5812-9315","authenticated-orcid":false,"given":"Hideki","family":"Nakasone","sequence":"additional","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1111\/bjh.18654","article-title":"Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies","volume":"200","author":"Minakata","year":"2023","journal-title":"Br. J. Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lawson, M.A., McDonald, M.M., Kovacic, N., Hua Khoo, W., Terry, R.L., and Down, J. (2015). Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat. Commun., 6.","DOI":"10.1038\/ncomms9983"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1182\/blood.2024024371","article-title":"EVIDENCE meta-analysis: Evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma","volume":"144","author":"Landgren","year":"2024","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4375","DOI":"10.1172\/JCI80325","article-title":"Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma","volume":"125","author":"Kikuchi","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Azab, A.K., Hu, J., Quang, P., Azab, F., Pitsillides, C., Awwad, R., Thompson, B., Maiso, P., Sun, J.D., and Hart, C.P. (2012). Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood, 119.","DOI":"10.1182\/blood-2011-09-380410"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/sj.leu.2402924","article-title":"Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms","volume":"17","author":"Nefedova","year":"2003","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.stem.2020.12.017","article-title":"Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption","volume":"28","author":"Mondala","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nara, M., Teshima, K., Watanabe, A., Ito, M., Iwamoto, K., Kitabayashi, A., Kume, M., Hatano, Y., Takahashi, N., and Iida, S. (2013). Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056954"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Osada, N., Kikuchi, J., Iha, H., Yasui, H., Ikeda, S., Takahashi, N., and Furukawa, Y. (2023). c-FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma. Clin. Transl. Med., 13.","DOI":"10.1002\/ctm2.1364"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Binder, M., Szalat, R.E., Talluri, S., Fulciniti, M., Avet-Loiseau, H., Parmigiani, G., Samur, M.K., and Munshi, N.C. (2024). Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes. Nat. Commun., 15.","DOI":"10.1038\/s41467-024-47793-5"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Okada, S., Fukuda, T., Inada, K., and Tokuhisa, T. (1999). Prolonged expression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells. Blood, 93.","DOI":"10.1182\/blood.V93.3.816"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ibneeva, L., Singh, S.P., Sinha, A., Eski, S.E., Wehner, R., Rupp, L., Kovtun, I., P\u00e9rez-Valencia, J.A., Gerbaulet, A., and Reinhardt, S. (2024). CD38 promotes hematopoietic stem cell dormancy. PLoS Biol., 22.","DOI":"10.1371\/journal.pbio.3002517"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1182\/bloodadvances.2022007291","article-title":"Extramedullary multiple myeloma originates from hyaluronan-induced homophilic cell-cell interactions of CD44 variant-expressing myeloma cells under shear stress","volume":"7","author":"Kikuchi","year":"2023","journal-title":"Blood Adv."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Barlogie, B., Anaissie, E., van Rhee, F., Haessler, J., Hollmig, K., Pineda-Roman, M., Cottler-Fox, M., Mohiuddin, A., Alsayed, Y., and Tricot, G. (2007). Incorporating bortezomib into upfront treatment for multiple myeloma: Early results of total therapy 3. Br. J. Haematol., 138.","DOI":"10.1111\/j.1365-2141.2007.06639.x"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Spencer, J.A., Ferraro, F., Roussakis, E., Klein, A., Wu, J., Runnels, J.M., Zaher, W., Mortensen, L.J., Alt, C., and Turcotte, R. (2014). Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature, 508.","DOI":"10.1038\/nature13034"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3995","DOI":"10.1111\/cas.15087","article-title":"Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma","volume":"112","author":"Ikeda","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.3892\/ijo.2013.2134","article-title":"Hypoxia reduces CD138 expression and induces an immature and stem cell-like transcriptional program in myeloma cells","volume":"43","author":"Kawano","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"34784","DOI":"10.18632\/oncotarget.26196","article-title":"Clinical impact of serum soluble SLAMF7 in multiple myeloma","volume":"9","author":"Ishibashi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3414","DOI":"10.3324\/haematol.2024.285368","article-title":"Soluble SLAMF7 is generated by alternative splicing in multiple myeloma cells","volume":"109","author":"Kikuchi","year":"2024","journal-title":"Haematologica"},{"key":"ref_20","first-page":"193","article-title":"SLAMF7 signaling reprograms T cells toward exhaustion in the tumor microenvironment","volume":"206","author":"Hyslop","year":"2020","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1038\/s41375-021-01172-x","article-title":"Selective elimination of immunosuppressive T cells in patients with multiple myeloma","volume":"35","author":"Awwad","year":"2021","journal-title":"Leukemia"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kulig, P., \u0141uczkowska, K., Machali\u0144ski, B., and Baumert, B. (2024). Deep hematologic response to RD treatment in patients with multiple myeloma is associated with overexpression of IL-17R in CD138+ plasma cells. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-74558-3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.3390\/cancers16172940","article-title":"Therapeutic antisense oligonucleotides in oncology: From bench to bedside","volume":"16","author":"Chery","year":"2024","journal-title":"Cancers"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/7\/474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:58:14Z","timestamp":1760029094000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/7\/474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,21]]},"references-count":23,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cells14070474"],"URL":"https:\/\/doi.org\/10.3390\/cells14070474","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,21]]}}}