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Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves
Sarah R Amend1, William C Wilson1, Liang Chu1
1Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States of America.
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.
Insights
Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). This study identified novel gene variants in mice that affect multiple cell types, suggesting MM development involves non-cell autonomous factors.
Area of Science:
- Genetics
- Immunology
- Oncology
Background:
- Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM), a plasma B-cell malignancy.
- The genetic underpinnings of MGUS and its progression to MM are not well understood.
- The C57BL/KaLwRij (KaLwRij) mouse strain exhibits high rates of benign idiopathic paraproteinemia (BIP), similar to MGUS and MM progression.
Purpose of the Study:
- To investigate the genetic basis of MGUS and its progression to MM using the KaLwRij mouse model.
- To identify novel genetic variants contributing to MM pathogenesis.
- To explore the cellular contributions to MM development.
Main Methods:
- Mouse haplotype analysis.
- Human multiple myeloma single nucleotide polymorphism (SNP) array data analysis.
- Whole exome and whole genome sequencing of KaLwRij mice.
Main Results:
- Identified novel KaLwRij gene variants, including Samsn1 deletion and deleterious point mutations in Tnfrsf22 and Tnfrsf23.
- These variants impacted B-cells, macrophages, and bone marrow stromal cells, all implicated in MM pathogenesis.
- Demonstrated that multiple cell types contribute to MM development before somatic driver mutations arise.
Conclusions:
- MM development may be an inherently non-cell autonomous malignancy.
- Germline genetic variants in multiple cell types can predispose to MM.
- The KaLwRij mouse model provides insights into the early stages of MM development.
