Abstract
Multiple myeloma, a plasma cell malignancy, is a genetically heterogeneous disease and the genetic factors that contribute to its development and progression remain to be fully elucidated. The tumour suppressor gene GLIPR1 has previously been shown to be deleted in approximately 10% of myeloma patients, to inhibit the development of plasma cell tumours in ageing mice and to have reduced expression levels in the plasma cells of patients with light-chain amyloidosis, a myeloma-related malignancy. Therefore, we hypothesised that GLIPR1 may have tumour suppressor activity in multiple myeloma. In this study, we demonstrate that plasma cell expression of GLIPR1 is reduced in the majority of myeloma patients and Glipr1 expression is lost in the 5TGM1 murine myeloma cell line. However, overexpression of GLIPR1 in a human myeloma cell line did not affect cell proliferation in vitro. Similarly, re-expression of Glipr1 in 5TGM1 cells did not significantly reduce their in vitro proliferation or in vivo growth in C57BL/KaLwRij mice. In addition, using CRISPR-Cas9 genome editing, we generated C57BL/Glipr1-/- mice and showed that loss of Glipr1 in vivo did not affect normal haematopoiesis or the development of monoclonal plasma cell expansions in these mice up to one year of age. Taken together, our results suggest that GLIPR1 is unlikely to be a potent tumour suppressor in multiple myeloma. However, it remains possible that the down-regulation of GLIPR1 may cooperate with other genetic lesions to promote the development of myeloma.
Highlights
Multiple myeloma (MM) is a haematological malignancy characterised by the uncontrolled proliferation of antibody-producing plasma cells (PCs) within the bone marrow (BM)
Given that the GLIPR1 tumour suppressor gene was found to have significantly reduced expression levels in PCs from patients with amyloidosis [40] and to be deleted in 9.4% of MM patients [39], we hypothesised that the expression of GLIPR1 may be down-regulated in the malignant PCs of MM patients
We show that GLIPR1 expression is significantly reduced in PCs from MM patients compared to normal controls, with the majority of MM patients having GLIPR1 mRNA levels below the normal range
Summary
Multiple myeloma (MM) is a haematological malignancy characterised by the uncontrolled proliferation of antibody-producing plasma cells (PCs) within the bone marrow (BM). MM is defined by the presence of 10% or more clonal PCs in the BM and one or more myelomadefining event(s) [1]. Myeloma-defining events include evidence of end-organ damage, such. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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