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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM\u2019s progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138<jats:sup>-<\/jats:sup> BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS)\u2009&lt;\u200918 months) or non-progressing (PFS\u2009&gt;\u20094 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of <jats:italic>GZMK<\/jats:italic><jats:sup><jats:italic>+<\/jats:italic><\/jats:sup> and <jats:italic>TIGIT<\/jats:italic><jats:sup>+<\/jats:sup> exhausted CD8<jats:sup>+<\/jats:sup> T-cells (<jats:italic>P<\/jats:italic>\u2009=\u20090.022) along with decreased expression of cytolytic markers (<jats:italic>PRF1, GZMB, GNLY<\/jats:italic>). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre\/Pro B cells), with elevated expression for markers of B cell development (<jats:italic>IGLL1<\/jats:italic>, <jats:italic>SOX4<\/jats:italic>, <jats:italic>DNTT<\/jats:italic>). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.<\/jats:p>","DOI":"10.1038\/s41525-022-00340-x","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T09:02:35Z","timestamp":1674723755000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Cross center single-cell RNA sequencing study of the immune microenvironment in rapid progressing multiple myeloma"],"prefix":"10.1038","volume":"8","author":[{"given":"William","family":"Pilcher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beena E.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati S.","family":"Bhasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2368-4890","authenticated-orcid":false,"given":"Reyka G.","family":"Jayasinghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6948-0626","authenticated-orcid":false,"given":"Edgar","family":"Gonzalez-Kozlova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra","family":"Dasari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghee","family":"Kim-Schulze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeeb","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1198-6341","authenticated-orcid":false,"given":"Jonathan","family":"Patton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Fiala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Cheloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taxiarchis","family":"Kourelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-5988","authenticated-orcid":false,"given":"Madhav V.","family":"Dhodapkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Vij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaadi","family":"Mehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hearn Jay","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Auclair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Avigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaji K.","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5643-9520","authenticated-orcid":false,"given":"Sacha","family":"Gnjatic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Bhasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"340_CR1","doi-asserted-by":"publisher","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","volume":"3","author":"SK Kumar","year":"2017","unstructured":"Kumar, S. 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