Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures and a preclinical model of the disease to examine the role of microRNA-mediated post-transcriptional regulation -focusing in particular on miR-203 and its target ABL1- in gastric MALT lymphomagenesis. Microarray-based microRNA expression profiling revealed a strong down-regulation of the putative tumor suppressor microRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared to matched adjacent normal material from the same patients. Treatment of lymphoma B-cells with demethylating agents led to increased miR-203 expression and the concomitant down-regulation of ABL1, confirming the epigenetic regulation of this microRNA. Ectopic re-expression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy.