c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment
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...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/7/474 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850184586064035840 |
|---|---|
| author | Naoki Osada Jiro Kikuchi Sae Matsuoka Hiroshi Yasui Sho Ikeda Naoto Takahashi Yusuke Furukawa Hideki Nakasone |
| author_facet | Naoki Osada Jiro Kikuchi Sae Matsuoka Hiroshi Yasui Sho Ikeda Naoto Takahashi Yusuke Furukawa Hideki Nakasone |
| author_sort | Naoki Osada |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b1a4c6c2e4e64f5ab048e17aeb8269c1 |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-b1a4c6c2e4e64f5ab048e17aeb8269c12025-08-20T02:17:00ZengMDPI AGCells2073-44092025-03-0114747410.3390/cells14070474c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow MicroenvironmentNaoki Osada0Jiro Kikuchi1Sae Matsuoka2Hiroshi Yasui3Sho Ikeda4Naoto Takahashi5Yusuke Furukawa6Hideki Nakasone7Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, JapanDivision of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, JapanDivision of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, JapanDepartment of Hematology & Oncology, St. Marianna University School of Medicine, Kawasaki 216-8511, JapanDepartment of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita 010-8543, JapanDepartment of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita 010-8543, JapanDivision of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, JapanDivision of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, JapanMultiple 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.https://www.mdpi.com/2073-4409/14/7/474c-FOSdrug resistancecancer stem cellbone marrow microenvironmentmultiple myeloma |
| spellingShingle | Naoki Osada Jiro Kikuchi Sae Matsuoka Hiroshi Yasui Sho Ikeda Naoto Takahashi Yusuke Furukawa Hideki Nakasone c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment Cells c-FOS drug resistance cancer stem cell bone marrow microenvironment multiple myeloma |
| title | c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment |
| title_full | c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment |
| title_fullStr | c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment |
| title_full_unstemmed | c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment |
| title_short | c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment |
| title_sort | c fos confers stem cell like features to multiple myeloma cells in a bone marrow microenvironment |
| topic | c-FOS drug resistance cancer stem cell bone marrow microenvironment multiple myeloma |
| url | https://www.mdpi.com/2073-4409/14/7/474 |
| work_keys_str_mv | AT naokiosada cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT jirokikuchi cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT saematsuoka cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT hiroshiyasui cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT shoikeda cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT naototakahashi cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT yusukefurukawa cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment AT hidekinakasone cfosconfersstemcelllikefeaturestomultiplemyelomacellsinabonemarrowmicroenvironment |