{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:01:05Z","timestamp":1783576865346,"version":"3.55.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007289","name":"Nanjing Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Multiple myeloma (MM) is a malignant plasma cell disease caused by abnormal proliferation of clonal plasma cells in bone marrow. Upfront identification of tumor subgroups with specific biological markers has the potential to improve biologically-driven therapy. Previously, we established a molecular classification by stratifying multiple myeloma into two subtypes with a different prognosis based on a gene module co-expressed with MCL-1 (MCL1-M).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene Ontology (GO) analysis with differentially expressed genes was performed to identify signal pathway. Drug sensitivity was analyzed using the OncoPredict algorithm. Drug sensitivity of different myeloma cell lines was detected by CCK8 and flow cytometry. RNA-seq was performed on drug-sensitive cell lines before and after adriamycin treatment. RT-qPCR was used to further verify the sequencing results. The expression of \u03b3-H2AX and dsDNA in sensitive and resistant cell lines was detected by immunofluorescence method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In our study, we demonstrated that MCL1-M low MM were more sensitive to anthracyclines. We treated different myeloma cell lines with doxorubicin <jats:italic>in vitro<\/jats:italic> and discovered the association of drug sensitivity with IFN signaling. Herein, we demonstrate that the doxorubicin-sensitive myeloma cell line showed significant DNA damage and up-regulated expression of genes related to the IFN response, which was not observed in drug-insensitive cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our results suggest that the active IFN signaling pathway may serve as a marker for predicting chemotherapy sensitivity in patients with myeloma. With our MCL1-M molecular classification system, we can screen patients with a potentially good response to the interferon signaling pathway and provide individualized treatment for MM. We propose IFN-a as adjuvant therapy for patients with myeloma sensitive to anthracyclines to further improve the therapeutic effect and prolong the survival of patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1357996","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T04:32:21Z","timestamp":1715315541000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Activated interferon response from DNA damage in multiple myeloma cells contributes to the chemotherapeutic effects of anthracyclines"],"prefix":"10.3389","volume":"14","author":[{"given":"Jin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuxia","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bitao","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianshu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiya","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuzhang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"58","DOI":"10.7861\/clinmedicine.19-1-58","article-title":"Haematology: multiple myeloma","volume":"19","author":"Firth","year":"2019","journal-title":"Clin Med (Lond)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-09-825331","article-title":"Toward personalized treatment in multiple myeloma based on molecular characteristics","volume":"133","author":"Pawlyn","year":"2019","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0362-z","article-title":"The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies","volume":"33","author":"Harding","year":"2019","journal-title":"Leukemia"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.01.041","article-title":"Comprehensive molecular tumor profiling in radiation oncology: how it could be used for precision medicine","volume":"382","author":"Eke","year":"2016","journal-title":"Cancer Lett"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2","article-title":"MCL1 gene co-expression module stratifies multiple myeloma and predicts response to proteasome inhibitor-based therapy","volume":"57","author":"Samo","year":"2018","journal-title":"Genes Chromosomes Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdi125","article-title":"Interferon-alpha as maintenance therapy in patients with multiple myeloma","volume":"16","author":"Schaar","year":"2005","journal-title":"Ann Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/028418600750063569","article-title":"Interferon in multiple myeloma\u2014summary of treatment results and clinical implications","volume":"39","author":"Ludwig","year":"2000","journal-title":"Acta Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1046\/j.1365-2141.1997.9942643.x","article-title":"Australian leukaemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma","volume":"97","author":"Joshua","year":"1997","journal-title":"Br J Haematol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.02575.x","article-title":"Wilfrid interferon \u03b1 extends the survival of human myeloma cells through an upregulation of the Mcl-1 anti-apoptotic molecule","volume":"112","author":"Puthier","year":"2001","journal-title":"Br J Haematol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/BF02796202","article-title":"Viewpoint on the impact of interferon in the treatment of multiple myeloma: benefit for a small proportion of patients","volume":"17","author":"Blad\u00e9","year":"2000","journal-title":"Med Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2174\/138945011794815329","article-title":"Interferon-alpha in the treatment of multiple myeloma","volume":"12","author":"Khoo","year":"2011","journal-title":"Curr Drug Targets"},{"key":"B13","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41591-018-0302-5","article-title":"Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss","volume":"25","author":"Liu","year":"2019","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00322","article-title":"Plasticity of Type I interferon-mediated responses in cancer therapy: from anti-tumor immunity to resistance","volume":"8","author":"Budhwani","year":"2018","journal-title":"Front Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nri3845","article-title":"Type I interferons in anticancer immunity","volume":"15","author":"Zitvogel","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3708","article-title":"Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy","volume":"20","author":"Sistigu","year":"2014","journal-title":"Nat Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.012","article-title":"DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity","volume":"42","author":"H\u00e4rtlova","year":"2015","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1182\/bloodadvances.2017013334","article-title":"Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma","volume":"2","author":"Merz","year":"2018","journal-title":"Blood Adv"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-849893","article-title":"RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib\/lenalidomide decision signature","volume":"132","author":"Chapman","year":"2018","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.39.6820","article-title":"Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65\/GMMG-HD4 trial","volume":"30","author":"Sonneveld","year":"2012","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"bbab260","DOI":"10.1093\/bib\/bbab260","article-title":"oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data","volume":"22","author":"Maeser","year":"2021","journal-title":"Brief Bioinform"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.06.017","article-title":"A landscape of pharmacogenomic interactions in cancer","volume":"166","author":"Iorio","year":"2016","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20220241","article-title":"LDNA sensing in cancer: pro-tumour and antitumour functions of cGAS-STING signalling","volume":"67","author":"Wheeler","year":"2023","journal-title":"Essays Biochem"},{"key":"B24","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13058-023-01652-1","article-title":"RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon\/STAT1 pro-apoptosis signaling","volume":"25","author":"Tolg","year":"2023","journal-title":"Breast Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2017.1413188","article-title":"DNA damage response-initiated cytokine secretion in bone marrow stromal cells promotes chemoresistance of myeloma cells","volume":"59","author":"Tang","year":"2018","journal-title":"Leuk Lymphoma"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2523","article-title":"GammaH2AX and cancer","volume":"8","author":"Bonner","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77443","article-title":"DNA damage independent inhibition of NF-\u03baB transcription by anthracyclines","volume":"11","author":"Chora","year":"2022","journal-title":"eLife"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1039\/d1np00059d","article-title":"Anthracyclines: biosynthesis, engineering and clinical applications","volume":"39","author":"Hulst","year":"2022","journal-title":"Nat Prod Rep"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-319-26666-4_1","article-title":"Staining against phospho-H2AX (\u03b3-H2AX) as a marker for DNA damage and genomic instability in cancer tissues and cells","volume":"899","author":"Nagelkerke","year":"2016","journal-title":"Adv Exp Med Biol"},{"key":"B30","article-title":"2AX \u2013 a novel biomarker for DNA double-strand breaks","volume":"22","author":"Kuo","year":"2008","journal-title":"In Vivo"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0014-2999(01)00765-8","article-title":"Voest Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review","volume":"415","author":"De Beer EL","year":"2001","journal-title":"Eur J Pharmacol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15583","article-title":"New insights into the activities and toxicities of the old anticancer drug doxorubicin","volume":"288","author":"van der Zanden","year":"2021","journal-title":"FEBS J"},{"key":"B33","doi-asserted-by":"publisher","first-page":"5688","DOI":"10.3390\/ijms23105688","article-title":"The role of DNA repair in genomic instability of multiple myeloma","volume":"23","author":"Ali","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4161\/cc.25951","article-title":"DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment","volume":"12","author":"Gourzones-Dmitriev","year":"2013","journal-title":"Cell Cycle"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0135-6","article-title":"At the intersection of DNA damage and immune responses","volume":"19","author":"Bednarski","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809242105","article-title":"An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer","volume":"105","author":"Weichselbaum","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5949","DOI":"10.3390\/cancers13235949","article-title":"Genome instability in multiple myeloma: facts and factors","volume":"13","author":"Aksenova","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-02-832576","article-title":"Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis","volume":"132","author":"Teoh","year":"2018","journal-title":"Blood"},{"key":"B39","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.ccell.2017.05.011","article-title":"ILF2 is a regulator of RNA splicing and DNA damage response in 1q21-amplified multiple myeloma","volume":"32","author":"Marchesini","year":"2017","journal-title":"Cancer Cell"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1357996\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T04:32:26Z","timestamp":1715315546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1357996\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":41,"alternative-id":["10.3389\/fonc.2024.1357996"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2024.1357996","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]},"article-number":"1357996"}}