{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:08:30Z","timestamp":1768525710627,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Cancer Biology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100032616","name":"STARR Cancer Consortium","doi-asserted-by":"crossref","award":["I3-A162"],"award-info":[{"award-number":["I3-A162"]}],"id":[{"id":"10.13039\/100032616","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["R01 CA188794"],"award-info":[{"award-number":["R01 CA188794"]}]},{"name":"National Cancer Institute","award":["R01CA276053"],"award-info":[{"award-number":["R01CA276053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  MEIS2 was identified biochemically as a substrate of cereblon (CRBN), a receptor of the CRL4\n                  <jats:sup>CRBN<\/jats:sup>\n                  E3 ubiquitin ligase required for the anti-myeloma activity of immunomodulatory drugs (IMiD)s and CELMoDs. However, its function in myeloma is unknown. We discovered that MEIS2 is aberrantly expressed in bone marrow myeloma cells (BMMC)s, and that high\n                  <jats:italic>MEIS2, CDK4 or CDK6<\/jats:italic>\n                  and low\n                  <jats:italic>CRBN<\/jats:italic>\n                  expression predisposes patients to inferior overall survival in IMiD therapy. Inhibition of CDK4\/6 (CDK4\/6i) reprograms BMMCs for IMiD vulnerability\n                  <jats:italic>ex vivo<\/jats:italic>\n                  that mimics patient\u2019s response to IMiDs. Mechanistically, CDK4\/6i both rapidly accelerates the displacement of MEIS2 from CRBN by IMiD and destabilizes the MEIS2 protein while increasing the CRBN protein in cooperation with IMiD and CELMoD. This enhances CRL4\n                  <jats:sup>CRBN<\/jats:sup>\n                  ubiquitination of IKZF3 and IKZF1 for degradation that exacerbates the loss of IRF4 to relieve IRF7 for induction of the interferon response, culminating in TRAIL-mediated apoptosis. Additionally, MEIS2 promotes BCMA expression and antagonizes repression of BCMA by IMiD and CELMoD for survival of myeloma cells. Thus, CDK4\/6i reverses MEIS2 inhibition of CRL4\n                  <jats:sup>CRBN<\/jats:sup>\n                  in cooperation with IMiD and CELMoD, and mitigates MEIS2-mediated BCMA signaling for survival, suggesting targeting MEIS2 and CDK4\/6 as a new strategy to advance immunomodulatory drug therapy in multiple myeloma.\n                <\/jats:p>","DOI":"10.1101\/2025.10.14.681840","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T18:20:16Z","timestamp":1760552416000},"source":"Crossref","is-referenced-by-count":0,"title":["CDK4\/6 Inhibition Reverses MEIS2 Suppression of CRL4\n                  <sup>CRBN<\/sup>\n                  to Enhance Immunomodulatory Drug Therapy in Multiple Myeloma"],"prefix":"10.64898","author":[{"given":"Xiangao","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Jayabalan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio Di","family":"Liberto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott A.","family":"Ely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomer M.","family":"Mark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Niesvizky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Selina","family":"Chen-Kiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025101705151348000_2025.10.14.681840v1.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-785246"},{"key":"2025101705151348000_2025.10.14.681840v1.2","doi-asserted-by":"crossref","first-page":"e448","DOI":"10.1016\/S2352-3026(19)30109-7","article-title":"Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial","volume":"6","year":"2019","journal-title":"Lancet Haematol"},{"key":"2025101705151348000_2025.10.14.681840v1.3","doi-asserted-by":"crossref","first-page":"e403","DOI":"10.1016\/S2352-3026(22)00103-X","article-title":"Addition of elotuzumab to lenalidomide and dexamethasone for patients with newly diagnosed, transplantation ineligible multiple myeloma (ELOQUENT-1): an open-label, multicentre, randomised, phase 3 trial","volume":"9","year":"2022","journal-title":"Lancet Haematol"},{"key":"2025101705151348000_2025.10.14.681840v1.4","doi-asserted-by":"crossref","unstructured":"Dimopoulos MA , et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. 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