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Published on: April 8, 2009
p53 regulates CD46 expression and measles virus infection in myeloma cells
Anne Lok1,2, Geraldine Descamps1, Benoit Tessoulin1,2
1CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.
Abstract:
In this study, we assessed the sensitivity of myeloma cells to the oncolytic measles virus (MV) in relation to p53 using 37 cell lines and 23 primary samples. We showed that infection and cell death were correlated with CD46 expression, which was associated with TP53 status; TP53 cell lines highly expressed CD46 and were preferentially infected by MV when compared with the TP53 cell lines (P = .046 and P = .045, respectively). Infection of myeloma cells was fully dependent on CD46 expression in both cell lines and primary cells. In the TP53 wt cell lines, but not the TP53 cell lines, activation of the p53 pathway with nutlin3a inhibited both CD46 expression and MV infection, while TP53 silencing reciprocally increased CD46 expression and MV infection. We showed using a p53 chromatin immunoprecipitation assay and microRNA assessment that CD46 gene expression was directly and indirectly regulated by p53. Primary myeloma cells overexpressed CD46 as compared with normal cells and were highly infected and killed by MV. CD46 expression and MV infection were inhibited by nutlin3a in primary p53-competent myeloma cells, but not in p53-deficient myeloma cells, and the latter were highly sensitive to MV infection. In summary, myeloma cells were highly sensitive to MV and infection inhibition by the p53 pathway was abrogated in p53-deficient myeloma cells. These results argue for an MV-based clinical trial for patients with p53 deficiency.
Insights
Myeloma cells are highly sensitive to oncolytic measles virus (MV) infection, especially when the p53 pathway is deficient. This suggests MV-based therapies could be effective for patients with p53-deficient myeloma.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Multiple myeloma is a hematologic malignancy characterized by uncontrolled plasma cell proliferation.
- Oncolytic viruses, such as measles virus (MV), are being investigated as a therapeutic strategy for various cancers.
- The tumor suppressor protein p53 plays a critical role in cellular response to DNA damage and stress.
Purpose of the Study:
- To assess the sensitivity of myeloma cells to oncolytic measles virus (MV) in relation to the p53 tumor suppressor pathway.
- To investigate the role of CD46 expression as a receptor for MV in myeloma cells and its correlation with p53 status.
- To explore the potential of MV as a therapeutic agent for p53-deficient myeloma.
Main Methods:
- Utilized 37 myeloma cell lines and 23 primary myeloma samples.
- Assessed MV infection, cell death, and CD46 expression in relation to TP53 status.
- Employed nutlin3a to activate the p53 pathway and TP53 silencing to evaluate its effects on CD46 expression and MV infection.
- Conducted p53 chromatin immunoprecipitation assays and microRNA assessments to elucidate CD46 gene regulation by p53.
Main Results:
- Myeloma cell infection and death by MV correlated with CD46 expression.
- TP53-deficient myeloma cell lines exhibited higher CD46 expression and preferential MV infection compared to TP53-wild-type lines.
- p53 pathway activation inhibited CD46 expression and MV infection in TP53-wild-type cells, while p53 silencing increased them.
- p53 directly and indirectly regulated CD46 gene expression.
- Primary myeloma cells overexpressed CD46, were highly infected by MV, and sensitive to MV-induced cell death.
- Nutlin3a inhibited MV infection in p53-competent primary myeloma cells but not in p53-deficient cells, which remained highly sensitive to MV.
Conclusions:
- Myeloma cells demonstrate high sensitivity to oncolytic measles virus.
- The p53 pathway modulates CD46 expression, influencing MV infectivity in myeloma cells.
- p53-deficient myeloma cells are particularly susceptible to MV infection, suggesting a potential therapeutic window.
- Results support the rationale for a measles virus-based clinical trial in patients with p53-deficient multiple myeloma.
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