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We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and\/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.<\/jats:p>","DOI":"10.1101\/2024.01.21.576547","type":"posted-content","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T13:06:24Z","timestamp":1706101584000},"source":"Crossref","is-referenced-by-count":1,"title":["Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-089X","authenticated-orcid":false,"given":"Zainul S.","family":"Hasanali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-5748","authenticated-orcid":false,"given":"Alfred L.","family":"Garfall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Burzenski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4868-1031","authenticated-orcid":false,"given":"Leonard D.","family":"Shultz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3616-5243","authenticated-orcid":false,"given":"Siddhant","family":"Kadu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9551-9491","authenticated-orcid":false,"given":"Neil C.","family":"Sheppard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek","family":"Dopkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2935-2566","authenticated-orcid":false,"given":"Dan T.","family":"Vogl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-3843","authenticated-orcid":false,"given":"Adam D.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"Waxman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0703-2518","authenticated-orcid":false,"given":"Sandra P.","family":"Susanibar-Adaniya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-3735","authenticated-orcid":false,"given":"Martin","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3935-6069","authenticated-orcid":false,"given":"Edward A.","family":"Stadtmauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9345-1502","authenticated-orcid":false,"given":"David","family":"Allman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024012703100920000_2024.01.21.576547v1.1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2020-0141"},{"key":"2024012703100920000_2024.01.21.576547v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-12-195008"},{"issue":"2","key":"2024012703100920000_2024.01.21.576547v1.3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41408-021-00414-6","article-title":"A clinical perspective on plasma cell leukemia; 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