{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:20:40Z","timestamp":1782278440135,"version":"3.54.5"},"reference-count":62,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In B-cell malignancies, the overexpression of MYC is associated with poor prognosis, but its mechanism underlying resistance to immunochemotherapy remains less clear. In further investigations of this issue, we show here that the pharmacological inhibition of MYC in various lymphoma and multiple myeloma cell lines, as well as patient-derived primary tumor cells, enhances their susceptibility to NK cell-mediated cytotoxicity induced by conventional antibodies targeting CD20 (rituximab) and CD38 (daratumumab), as well as T cell-mediated cytotoxicity induced by the CD19-targeting bispecific T-cell engager blinatumomab. This was associated with upregulation of the target antigen only for rituximab, suggesting additional escape mechanisms. To investigate these mechanisms, we targeted the MYC gene in OCI-LY18 cells using CRISPR-Cas9 gene-editing technology. CRISPR-Cas9-mediated MYC targeting not only upregulated CD20 but also triggered broader apoptotic pathways, upregulating pro-apoptotic PUMA and downregulating anti-apoptotic proteins BCL-2, XIAP, survivin and MCL-1, thereby rendering tumor cells more prone to apoptosis, a key tumor-lysis mechanism employed by T-cells and NK-cells. Moreover, MYC downregulation boosted T-cell activation and cytokine release in response to blinatumomab, revealing a MYC-mediated T-cell suppression mechanism. In conclusion, MYC overexpressing tumor cells mitigated the efficacy of therapeutic antibodies through several non-overlapping mechanisms. Given the challenges associated with direct MYC inhibition due to toxicity, successful modulation of MYC-mediated immune evasion mechanisms may improve the outcome of immunotherapeutic approaches in B-cell malignancies.<\/jats:p>","DOI":"10.3390\/ijms252212094","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T03:52:07Z","timestamp":1731297127000},"page":"12094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Delineating MYC-Mediated Escape Mechanisms from Conventional and T Cell-Redirecting Therapeutic Antibodies"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-1762","authenticated-orcid":false,"given":"Anna Vera","family":"de Jonge","sequence":"first","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Csik\u00f3s","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"Eken","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elianne P.","family":"Bulthuis","sequence":"additional","affiliation":[{"name":"Department of Clinical Human Genetics, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pino J.","family":"Poddighe","sequence":"additional","affiliation":[{"name":"Department of Clinical Human Genetics, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaretha G. M.","family":"Roemer","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-9182","authenticated-orcid":false,"given":"Martine E. D.","family":"Chamuleau","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuna","family":"Mutis","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nrc1393","article-title":"Analysis of genomic targets reveals complex functions of MYC","volume":"4","author":"Patel","year":"2004","journal-title":"Nat. Rev. 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