title: Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice.
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.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Srinivas
authors.identifier: 0000-0001-6827-2908
authors.initials: S
authors.lastname: Koduru
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Anja
authors.initials: A
authors.lastname: Hafemann
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hopf
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mehmet H
authors.initials: MH
authors.lastname: Kocoglu
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsotti
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Andrew
authors.identifier: 0000-0002-3868-9267
authors.initials: A
authors.lastname: Branagan
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eynon
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
mesh_terms: D000818:Animals; D001853:Bone Marrow; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009101:Multiple Myeloma; D009368:Neoplasm Transplantation; D010950:Plasma Cells / Q000166:cytology*; D011230:Precancerous Conditions; D059016:Tumor Microenvironment