MerTK is Ectopically Expressed and Affects the Biological Function in Diffuse Large B-Cell Lymphoma

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients do not receive standard rescue treatment; therefore, the exploration of new therapeutic targets for the treatment of DLBCL is urgently needed. Immunohistochemistry and western blotting were performed to determine the expression of MerTK in DLBCL. Targeted knockdown of MerTK by shRNA was conducted in DLBCL cell lines. DLBCL cell-derived xenograft models were established to evaluate the effects of MerTK in vivo. We found for the first time that MerTK, a proto-oncogene, is aberrantly highly expressed in DLBCL samples and cell lines. Targeted knockdown of MerTK or application of UNC2025, a small inhibitor of MerTK, can inhibit DLBCL cell proliferation, promote apoptosis, and inhibit G2/M phase arrest. Transcriptome sequencing was performed after targeted knockdown of MerTK, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the differentially expressed genes involved in the autophagy pathway, in which the expression of ANXA1 was significantly upregulated, were significantly enriched. Further studies revealed that targeted MerTK knockdown inhibited autophagy flow by increasing the expression of ANXA1 in DLBCL cells. Overexpression of ANXA1 decreased proliferation and autophagy flow in DLBCL cells. Targeted knockdown of MerTK decreased disease progression in a mouse xenograft DLBCL model in vivo. UNC2025 inhibited tumor growth in a DLBCL cell-derived xenograft model. Therefore, MerTK is ectopically expressed in DLBCL, and targeted inhibition of MerTK suppresses the growth of DLBCL in vitro and in vivo. This study provides clues for precision therapy for DLBCLs that target MerTK.