Abstract ARS-interacting multifunctional protein 2 (AIMP2), the component of aminoacyl-tRNA synthase complex, acts as a potent tumor suppressor in conjunction with p53. The second exon deficient AIMP2 generated by alternative splicing mechanism (AIMP2-DX2) induces loses its important role as a signaling modulator. Previously, it predisposes mouse to increase lung cancer, but it did not induce tumorigenesis by itself. To further validate the oncogenic role of AIMP2-DX2 in mouse model, we generated inducible transgenic mouse which express DX2 in doxycycline dependent manner. Unexpectedly, we report the late onset spontaneous lymphoma development instead of lung cancer in this model. Polyclonal expansion of pre-B cells and infiltration to multi-organ, especially kidney, was major events. More importantly, switching off the transgene by doxycycline removal reduced pre-B cell hyperplasia by inducing apoptotic cell death. Destabilization of p53 and dysregulation of cell cycle gene by DX2 overexpression underlined the increased lymphoid cell proliferation. Coincident with the results, in International Cancer Genome Consortium (ICGC) data analysis, AIMP2-DX2 expression was the highest in Burkitt lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) among various cancer subtypes. When analysis was performed using RNA sequencing data of various B-cell lymphoid malignancies, germinal B-cell origin (GCB) DLBCL, B-acute lymphoid leukemia and BL showed completely different gene expression pattern according to the AIMP2-DX2 expression status suggesting a distinct disease entity. AIMP2-DX2 expression in DLBCL cell line and tissue samples was validated and regulation of DX2 in lymphoma cell line affected cell viability as well as p53 stability. Lastly, we confirmed expression of AIMP2-DX2 in FFPE tissue of 35 lymphoma patients using RNA in situ hybridization (ISH) with specifically designed probes that capture the exon 1-3 junction of AIMP2 transcript. In summary, our data demonstrate the causality of AIMP2-DX2 in lymphoma oncogenesis and provide evidence that AIMP2-DX2 is a potential therapeutic target especially in DLBCL and BL. Figure. Figure. Disclosures No relevant conflicts of interest to declare.