{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:55:37Z","timestamp":1790949337245,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T00:00:00Z","timestamp":1692057600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin\u2010dependent degradation of IKZF1 and subsequent down\u2010regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates <jats:italic>IRF4<\/jats:italic> and other oncogenes in MM cells, suggesting the involvement of unknown co\u2010factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the <jats:italic>IRF4<\/jats:italic> gene to maintain its transcription after IKZF1 degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To identify unknown components of the IKZF1 complex, we analyzed the genome\u2010wide binding of IKZF1 in MM cells using chromatin immunoprecipitation\u2010sequencing (ChIP\u2010seq) and screened for the co\u2010occupancy of IKZF1 with other DNA\u2010binding factors on the myeloma genome using the ChIP\u2010Atlas platform.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that c\u2010FOS, a member of the activator protein\u20101 (AP\u20101) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome\u2010wide screening revealed the co\u2010occupancy of c\u2010FOS with IKZF1 on the regulatory regions of IKZF1\u2010target genes, including <jats:italic>IRF4<\/jats:italic> and <jats:italic>SLAMF7<\/jats:italic>, in MM cells but not normal bone marrow progenitors, pre\u2010B cells or mature T\u2010lymphocytes. c\u2010FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein\u2010protein interactions. The complex also includes c\u2010JUN and IKZF3 but not IRF4. Treatment of MM cells with short\u2010hairpin RNA against <jats:italic>FOS<\/jats:italic> or a selective AP\u20101 inhibitor significantly enhanced the anti\u2010MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP\u20101 inhibitor mitigated the lenalidomide resistance of MM cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>C\u2010FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co\u2010factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1364","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T14:32:27Z","timestamp":1692369147000},"source":"Crossref","is-referenced-by-count":12,"title":["c\u2010FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma"],"prefix":"10.1002","volume":"13","author":[{"given":"Naoki","family":"Osada","sequence":"first","affiliation":[{"name":"Division of Stem Cell Regulation Center for Molecular Medicine Jichi Medical University  Tochigi 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