title: Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types.
abstract: Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Amend
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Wilson
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Chu
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, United States of America.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serie
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Dingyan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gramolini
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: O'Neal
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hurchla
authors.affiliation: Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Graham
authors.initials: G
authors.lastname: Colditz
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; C000596182:SLy2 protein, mouse; C469948:Tnfrh2 protein, mouse