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High frequency of inactivating tetraspanin CD37 mutations in diffuse large B-cell lymphoma at immune-privileged sites

Suraya Elfrink, Charlotte M de Winde, Michiel van den Brand, Madeleine Rosa Berendsen, Margaretha Roemer, Frank Arnold, Luuk Janssen, Alie van der Schaaf, Erik Jansen, Patricia JTA Groenen, Astrid Eijkelenboom, Wendy B.C. Stevens, Corine J Hess, Johan HJM Han van Krieken, Joost S Vermaat, Arjen Cleven, Ruben AL de Groen, Viviana Neviani, Daphne De Jong, Sjoerd van Deventer, Blanca Scheijen and Annemiek van Spriel

Key Points

  • Loss-of-function mutations in CD37 occur predominantly in diffuse large B-cell lymphoma at immune-privileged sites.

  • CD37-mutated lymphoma B-cells show impaired CD37 cell surface localization, which may have implications for anti-CD37 therapies.

Abstract

Tetraspanin CD37 is predominantly expressed on the cell surface of mature B-lymphocytes, and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37-knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37 mutation analysis was performed in a cohort of 137 primary DLBCL, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) originating in testis or central nervous system. CD37 mutations were exclusively identified in IP-DLBCL cases (10/44, 23%), but absent in non-IP-DLBCL cases. The aberrations included ten missense mutations, one deletion, and three splice-site CD37 mutations. Modeling and functional analysis of CD37 missense mutations revealed loss-of-function by impaired CD37 protein expression at the plasma membrane of human lymphoma B-cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL, and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37 mutations.

  • Submitted April 18, 2019.
  • Revision received July 29, 2019.
  • Accepted July 20, 2019.