miR-28 plus ibrutinib as a novel combination therapy for Diffuse Large B Cell Lymphoma

ABSTRACT Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton’s tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients. STATEMENT OF SIGNIFICANCE This study demonstrates that a miRNA-based combination therapy with ibrutinib is superior to both monotherapies in DLBCL. miR-28 plus ibrutinib combined therapy inhibits DLBCL growth through the induction of a transcriptional program that impairs DNA replication. Our results provide a new gene signature with prognostic value for ABC-DLBCL.