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Gastric marginal zone B-cell lymphoma of MALT type (MALT lymphoma) arises in the context of chronic inflammation induced by the bacterial pathogen Helicobacter pylori. Although generally considered an indolent disease, MALT lymphoma may transform to gastric diffuse large B-cell lymphoma (gDLBCL) through mechanisms that remain poorly understood. By comparing microRNA expression profiles of gastric MALT lymphoma and gDLBCL, we have identified a signature of 27 deregulated microRNAs(miRNAs) that share the characteristic of being transcriptionally repressed by Myc. Myc overexpression was consequently detected in 80% of gDLBCL but only 20% of MALT lymphomas spotted on a tissue microarray. A highly similar signature of Myc-repressed miRNAs was further detected in nodal DLBCL. Small interfering RNA-mediated knock-down of Myc blocked proliferation of DLBCL cell lines. Of the Myc-repressed miRNAs down-regulated in malignant lymphoma, miR-34a showed the strongest antiproliferative properties when overexpressed in DLBCL cells. We could further attribute miR-34a's tumor-suppressive effects to deregulation of its target FoxP1. FoxP1 overexpression was detected in gDLBCL but not in gastric MALT lymphoma; FoxP1 knock-down efficiently blocked DLBCL proliferation. In conclusion, our results elucidate a novel Myc- and FoxP1-dependent pathway of malignant transformation and suggest miR-34a replacement therapy as a promising strategy in lymphoma treatment.