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miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

Nahikari Bartolomé-Izquierdo, Virginia G. de Yébenes, Angel F. Álvarez-Prado, Sonia M. Mur, Juan A. Lopez del Olmo, Sergio Roa, Jesus Vazquez and Almudena R R. Ramiro

Key points

  • miR-28 is a regulator of the Germinal Center reaction that dampens BCR signaling and impairs B cell proliferation and survival.

  • miR-28 has anti-tumoral activity in Burkitt and Diffuse Large B Cell lymphomas.

Abstract

Non-Hodgkin Lymphoma (NHL) comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific microRNA whose expression is lost in numerous mature B cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing CSR and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell cycle and B cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 re-expression in human Burkitt (BL) and Diffuse Large B cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment.

  • Submitted August 1, 2016.
  • Accepted February 1, 2017.