p53 regulates CD46 expression and measles virus infection in myeloma cells

Anne Lok 1, 2 Géraldine Descamps 1 Benoit Tessoulin 1, 2 David Chiron 1 Marion Eveillard 1, 3 Catherine Godon 3 Yannick Le Bris 1, 3 Astrid Vabret 4 Céline Bellanger 1 Laurent Maillet 5 Sophie Barilí E-Nion 5 Marc Gregoire 6 Jean-François Fonteneau 6 Steven Le Gouill 1, 2 Philippe Moreau 7, 2 Frederic Tangy 8 Martine Amiot 9 Agnès Moreau-Aubry 9 Catherine Deceunynck 9, *
* Corresponding author
1 CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
2 Unité d'Investigation Clinique - Service d'Hématologie Clinique [CHU Nantes]
3 Laboratoire d'Hematologie [CHU de Nantes]
4 Service de Virologie [CHU Caen]
5 CRCINA - Département ONCO - Equipe 8 - Stress Adaptation and Tumor Escape in breast cancer - SATE
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
6 CRCINA - Département INCIT - Equipe 4 - Mort cellulaire immunogénique appliquée aux traitements du mésothéliome
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
7 CRCINA - Département NOHMAD - Equipe 11 - Integrative oncogenomics of multiple myeloma pathogenesis and progression
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
8 Génomique virale et vaccination
9 CRCINA - Département NOHMAD - Equipe 10 - Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
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 abn cell lines highly expressed CD46 and were preferentially infected by MV when compared with the TP53 wt 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 abn 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.
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PASTEUR | CNRS | UNIV-ANGERS | COMUE-NORMANDIE | CRCINA | UNIV-NANTES | DIEUDONNE

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Anne Lok, Géraldine Descamps, Benoit Tessoulin, David Chiron, Marion Eveillard, et al.. p53 regulates CD46 expression and measles virus infection in myeloma cells. Blood Advances, The American Society of Hematology, 2018, 2 (23), pp.3492-3505. ⟨10.1182/bloodadvances.2018025106⟩. ⟨inserm-01957487⟩

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