{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:58:35Z","timestamp":1789016315476,"version":"build-2803163510"},"reference-count":59,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,5,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed\/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020003541","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T09:24:27Z","timestamp":1620293067000},"page":"2391-2402","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":21,"title":["Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma"],"prefix":"10.1182","volume":"5","author":[{"given":"Stephan R.","family":"Bohl","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6080-6175","authenticated-orcid":false,"given":"Laura K.","family":"Schmalbrock","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"},{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"},{"name":"Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Bauhuf","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dolnik","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Szyska","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-1261","authenticated-orcid":false,"given":"Tamara J.","family":"Bl\u00e4tte","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kn\u00f6dler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1474-8039","authenticated-orcid":false,"given":"Linda","family":"R\u00f6hner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Kull","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Langer","sequence":"additional","affiliation":[{"name":"Department of Hematology, Internal Oncology and Palliative Care, Kempten Hospital, Kempten, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"D\u00f6hner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Letai","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Damm","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Heckl","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Children\u2019s Hospital, Halle University Hospital, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bullinger","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany;"},{"name":"Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4649-0506","authenticated-orcid":false,"given":"Jan","family":"Kr\u00f6nke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany;"},{"name":"Department of Hematology, Oncology and Tumor Immunology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, 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