{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:02:36Z","timestamp":1753884156954,"version":"3.41.2"},"reference-count":54,"publisher":"The Company of Biologists","issue":"7","license":[{"start":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T00:00:00Z","timestamp":1626307200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007170","name":"Ministry of Economy","doi-asserted-by":"crossref","award":["PI19\/01320"],"award-info":[{"award-number":["PI19\/01320"]}],"id":[{"id":"10.13039\/501100007170","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI16\/01","898"],"award-info":[{"award-number":["PI16\/01","898"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"crossref","award":["IDEAS098VILL-IDEAS16"],"award-info":[{"award-number":["IDEAS098VILL-IDEAS16"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"crossref","award":["799850"],"award-info":[{"award-number":["799850"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Extramedullary multiple myeloma (EMM) has an overall survival of 6\u2005months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl\/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH\/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper\/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.<\/jats:p>","DOI":"10.1242\/dmm.048223","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T10:24:44Z","timestamp":1620987884000},"source":"Crossref","is-referenced-by-count":5,"title":["Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular and therapeutic studies"],"prefix":"10.1242","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3168-1940","authenticated-orcid":false,"given":"Lourdes","family":"Farre","sequence":"first","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Sanz","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet del Llobregat Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neus","family":"Ruiz-Xivill\u00e9","sequence":"additional","affiliation":[{"name":"Hematological Laboratory, Germans Trias i Pujol Hospital, Catalan Institute of Oncology, 08916 Badalona, Barcelona, Spain"},{"name":"Cancer and Leukemia Epigenetics and Biology and Experimental and Clinical Hematology Programs, Josep Carreras Leukaemia Research Institute, 08916 Badalona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Castro de Moura","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology and Experimental and Clinical Hematology Programs, Josep Carreras Leukaemia Research Institute, 08916 Badalona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Francisco","family":"Martin-Tejera","sequence":"additional","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Gon\u00e7alves-Ribeiro","sequence":"additional","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Martinez-Iniesta","sequence":"additional","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Calaf","sequence":"additional","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose","family":"Luis Mosquera","sequence":"additional","affiliation":[{"name":"IDIBELL Bioinformatic Unit \u2013 Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Ignacio","family":"Mart\u00edn-Subero","sequence":"additional","affiliation":[{"name":"Biomedical Epigenomics Group, Institut d'investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain"},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, 08010 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Granada","sequence":"additional","affiliation":[{"name":"Hematological Laboratory, Germans Trias i Pujol Hospital, Catalan Institute of Oncology, 08916 Badalona, Barcelona, Spain"},{"name":"Cancer and Leukemia Epigenetics and Biology and Experimental and Clinical Hematology Programs, Josep Carreras Leukaemia Research Institute, 08916 Badalona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-6093","authenticated-orcid":false,"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology and Experimental and Clinical Hematology Programs, Josep Carreras Leukaemia Research Institute, 08916 Badalona, Barcelona, Spain"},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, 08010 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Cancer, Carlos III Institute of Health, 28029 Madrid, Spain"},{"name":"Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Domingo-Domenech","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet del Llobregat Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fina","family":"Climent","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Cancer, Carlos III Institute of Health, 28029 Madrid, Spain"},{"name":"Department of Pathology, Hospital Universitari de Bellvitge \u2013 Bellvitge Biomedical Research Institute, 08907 L'Hospitalet de Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Villanueva","sequence":"additional","affiliation":[{"name":"Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain"},{"name":"Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 L'Hospitalet de Llobregat, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sureda","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet del Llobregat Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,7,15]]},"reference":[{"key":"2021071508252399600_DMM048223C1","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1101\/gr.180240.114","article-title":"Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers","volume":"25","author":"Agirre","year":"2015","journal-title":"Genome Res."},{"key":"2021071508252399600_DMM048223C2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.3324\/haematol.2013.088211","article-title":"Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy 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