MicroRNA-155 (MiR-155) is involved in normal B-cell development and lymphomagenesis, affecting cell differentiation, motility, and intracellular signaling. In this study, we searched for new targets of miR-155 potentially involved in the deregulation of the B-cell receptor pathway (BCR) in diffuse large B-cell lymphoma (DLBCL). We show that miR-155 represses DEPTOR (an mTOR phosphatase) and c-CBL (SYK ubiquitin E3 ligase) through direct 3’UTR interactions. In primary DLBCLs, miR-155 exhibits a reciprocal expression pattern with DEPTOR and c-CBL. Inhibition of miR-155 decreased expression of NFκB target genes and sensitized DLBCL cells to ibrutinib, confirming miR-155 role in the modulation of BCR signaling. Since the function of DEPTOR in DLBCLs has never been addressed, we first evaluated its expression in a series of 76 newly diagnosed DLBCL patients. DEPTOR protein expression was markedly lower in more aggressive non-germinal center-like (non-GCB) DLBCLs than in GCB tumors. In cell line models, inhibition of DEPTOR expression favored the migration of DLBCL cells toward the CXCL12 gradient. Finally, loss or gain of DEPTOR modulated the expression of specific proinflammatory cytokines and chemokines. Taken together, we identified DEPTOR as a new miR-155 target, which is differentially expressed between GCB- and non-GCB-type DLBCLs, and modulates cell migration and cytokine expression in DLBCL cells.Copyright © 2020. Published by Elsevier Inc.