Abstract
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.
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Acknowledgements
This work was supported by funds from the US National Institutes of Health (CA156689, CA106802, CA197603) and the clinical research priority program of the University of Zurich. The authors thank F. Giráldez-López, I. Tikhonova, S. Mane and M. Youngblood for assistance with sequencing analyses and C. Weibel, J. Alderman and C. Foster (all at Yale School of Medicine) for assistance with mouse colonies.
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M.V.D. and R.A.F. conceived and supervised the overall project, designed experiments and analyzed results. R.D., T.S. and R.V. designed and performed experiments and analyzed data. S.K., A.H., S.H., M.H.K., C.B., L.Z. and A.B. performed experiments and analyzed data. E.E. and M.G.M. designed experiments and analyzed data. M.V.D., R.D., T.S., R.V., M.G.M. and R.A.F. wrote the manuscript.
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Das, R., Strowig, T., Verma, R. et al. Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nat Med 22, 1351–1357 (2016). https://doi.org/10.1038/nm.4202
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DOI: https://doi.org/10.1038/nm.4202
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