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Transl. Med."],"published-print":{"date-parts":[[2025,11,19]]},"abstract":"<jats:p>\n                    The initiation and progression of multiple myeloma (MM) are intricate processes, and a critical challenge lies in understanding the mechanisms of malignant transformation in MM-initiating cells (MICs) and their driver genes. In this study, we used single-cell sequencing and genetic tracer analysis at each developmental stage, from hematopoietic stem cells to lymphoid lineage differentiation, to identify abnormal differentiation stages in patients with MM. We found that chromosome 1q amplification (1q\n                    <jats:sup>Amp<\/jats:sup>\n                    ) originated from a specific subgroup of B cells, whereas chromosome 17p deletion occurred at the plasma cell stage. 1q\n                    <jats:sup>Amp<\/jats:sup>\n                    was present in CD24\n                    <jats:sup>\u2212<\/jats:sup>\n                    FCRL5\n                    <jats:sup>+<\/jats:sup>\n                    B cell subgroups and initiated B cell transformation into malignant plasma cells by enhancing B cell proliferation and promoting plasma cell differentiation in vitro and in vivo. FCRL5 facilitated B cell differentiation into malignant plasma cells through its interaction with the IRF4\/SPI1 complex. The use of targeted FCRL5 CAR T cells in patients with relapsed or refractory MM (RRMM) showed promising safety and efficacy. Together, our work identified genetic events linked to the initiation and malignant transformation of MM along the B cell lineage. These findings form the foundation for identifying potential therapeutic strategies for patients with RRMM by targeting MICs and their driving oncogenes.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adu0114","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:59:24Z","timestamp":1763578764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Targeting the origins of multiple myeloma along hematopoietic stem cell lymphoid lineage differentiation"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5908-492X","authenticated-orcid":true,"given":"Jiaojiao","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, National Clinical Research Center for Geriatric Disorders, FuRong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China."},{"name":"Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5711-6416","authenticated-orcid":true,"given":"Yaru","family":"Li","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7856-2651","authenticated-orcid":true,"given":"Zhiling","family":"Yan","sequence":"additional","affiliation":[{"name":"Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4298-4752","authenticated-orcid":true,"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Hematology &amp; Blood Diseases Hospital, Chinese Academy of Medical Science &amp; Peking Union Medical College, Tianjin 300074, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-5925","authenticated-orcid":true,"given":"Zhenhao","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjiang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, National Clinical Research Center for Geriatric Disorders, FuRong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, National Clinical Research Center for Geriatric Disorders, FuRong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihan","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, National Clinical Research Center for Geriatric Disorders, FuRong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7984-9560","authenticated-orcid":true,"given":"Yinghong","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, National Clinical Research Center for Geriatric Disorders, FuRong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshuang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences\/Peking Union Medical College, Beijing 100005, P.R. 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