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Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice

Nature Medicine volume 22, pages 1351–1357 (2016)Cite this article

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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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Figure 1: Engraftment and phenotype of human plasma cell tumors in MIS(KI)TRG6 mice.
Figure 2: Engraftment of different tumor cellular compartments, the spectrum of non-malignant cells that engrafted and the potential for serial transplantation.
Figure 3: Pattern of tumor cell growth from a spectrum of clonal plasma cell tumors and preneoplastic lesions.
Figure 4: Comparison of the MIS(KI)TRG6 and SCID-hu models for the growth of preneoplastic gammopathies.
Figure 5: Genomic analysis of tumor cells engrafted in MIS(KI)TRG6 mice.
Figure 6: Analysis of somatic non-synonymous variants (SNVs).

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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.

Author information

Author notes

  1. Till Strowig

    Present address: Present address: Helmholtz Centre for Infection Research, Braunschweig, Germany.,

  2. Rituparna Das, Till Strowig and Rakesh Verma: These authors contributed equally to this work.

  3. Richard A Flavell and Madhav V Dhodapkar: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Rituparna Das, Rakesh Verma, Srinivas Koduru, Mehmet H Kocoglu, Lin Zhang, Andrew Branagan & Madhav V Dhodapkar

  2. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Till Strowig, Anja Hafemann, Stephanie Hopf, Elizabeth Eynon, Richard A Flavell & Madhav V Dhodapkar

  3. Division of Hematology, University Hospital Zurich, Zurich, Switzerland

    Chiara Borsotti & Markus G Manz

  4. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard A Flavell

  5. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA

    Madhav V Dhodapkar

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  1. Rituparna Das
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Contributions

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.

Corresponding authors

Correspondence to Richard A Flavell or Madhav V Dhodapkar.

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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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