Abstract
Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138+/CD38high cells from 40% of patients (8/20) led to a repopulation of CD19+CD38low or CD138+CD38+ B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19+CD38low xenografts were detected in human bone-bearing mice transplanted with CD19+CD38low/− B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138+CD38high cells demonstrated that (CD45low/− or CD19−) CD38high/CD138+ plasma cells, but not (CD45high or CD19+) CD38high/CD138+ plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19−CD138+, revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19−CD45low/− fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not.
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Acknowledgements
We thank Dr Stanley Schrier for facilitating the collaboration allowing us to obtain samples of patient bone marrow; Julia Kamp, Rhonda Hewitt and James Puni for obtaining patient consent and clinical specimens; Libuse Jerabek, Theresa Storm and Adriane Mosley for laboratory and mouse management. We especially thank Drs Stephen Willingham, Seth Karten, Ingrid Ibarra and the late Angela Lee for critical comments and the editing of the manuscript. In addition, we thank patients who consented to donate specimens. A part of this research was presented in the 101st AACR meeting in 2010 and in the Lymphoma and Myeloma 2011. Dongkyoon Kim was financially supported by the Irvington Institute Fellowship Program of the Cancer Research Institute (initially by the Irvington Institute for Immunological Research and The Dana Foundation). This research was supported by co-sponsorship (SPO no.: 43710) of the Multiple Myeloma Research Foundation and the Leukemia Lymphoma Society, and by the Ludwig Institute. Irving Weissman is a Daniel K and Virginia Ludwig Professor at Stanford.
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Irving L Weissman was a member of the scientific advisory board of Amgen and owns significant Amgen stock; he is a cofounder and director of Stem Cells, Inc. and cofounded Cellerant, Inc. These companies are not in the cancer stem cell field or, if they are now, they were not while Irving L Weissman was an advisor or held stock. The other authors declare no conflict of interest.
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Kim, D., Park, C., Medeiros, B. et al. CD19−CD45low/−CD38high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia 26, 2530–2537 (2012). https://doi.org/10.1038/leu.2012.140
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DOI: https://doi.org/10.1038/leu.2012.140
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