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VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced\/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition\u2013based therapies for treating advanced\/relapsed MM.<\/jats:p>","DOI":"10.1182\/blood.2020007156","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T18:59:55Z","timestamp":1594234795000},"page":"61-74","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":32,"title":["Expression of <i>Nras<\/i>\n                  <i>Q61R<\/i> and <i>MYC<\/i> transgene in germinal center B cells induces a highly malignant multiple myeloma in mice"],"prefix":"10.1182","volume":"137","author":[{"given":"Zhi","family":"Wen","sequence":"first","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9251-0416","authenticated-orcid":false,"given":"Adhithi","family":"Rajagopalan","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan D.","family":"Flietner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Yun","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4024-8225","authenticated-orcid":false,"given":"Marta","family":"Chesi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinlan","family":"Furumo","sequence":"additional","affiliation":[{"name":"Blood Research Institute, Versiti, Milwaukee, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Burns","sequence":"additional","affiliation":[{"name":"Blood Research Institute, Versiti, Milwaukee, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-2586","authenticated-orcid":false,"given":"Athanasios","family":"Papadas","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A.","family":"Ranheim","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"Pagenkopf","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary T.","family":"Morrow","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remington","family":"Finn","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Li","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9996-1466","authenticated-orcid":false,"given":"Xiaona","family":"You","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Jensen","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI; 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