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

in Hematological oncology by Yan Li, Cunzhen Shi, Jiazhuo Wu, Xiaoyan Feng, Wenting Song, Mengyuan Jin, Yu Chang, Lijuan Han, Ping Zhang, Yuqin Song, Jun Zhu, Mingzhi Zhang

TLDR

  • The study found that MerTK is aberrantly highly expressed in DLBCL and that targeting it may be a promising strategy for precision therapy.
  • Targeted knockdown of MerTK or application of UNC2025 can inhibit DLBCL cell proliferation, promote apoptosis, and inhibit G2/M phase arrest.
  • Further studies are needed to fully elucidate the mechanisms and clinical relevance of targeting MerTK in DLBCL.

Abstract

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.

Overview

  • The study aimed to investigate the expression and function of MerTK in diffuse large B-cell lymphoma (DLBCL) and explored its potential as a therapeutic target.
  • The researchers used immunohistochemistry, western blotting, and targeted knockdown of MerTK by shRNA in DLBCL cell lines to determine its expression and functional significance.
  • The study primarily aimed to identify a new therapeutic target for DLBCL patients who do not respond to standard rescue treatments.

Comparative Analysis & Findings

  • The study found that MerTK is aberrantly highly expressed in DLBCL samples and cell lines, suggesting that it may play a crucial role in the development and progression of the disease.
  • Targeted knockdown of MerTK or application of UNC2025, a small inhibitor of MerTK, showed promising results in inhibiting DLBCL cell proliferation, promoting apoptosis, and inhibiting G2/M phase arrest.
  • Transcriptome sequencing and KEGG analysis revealed that the differentially expressed genes involved in the autophagy pathway were significantly enriched, with ANXA1 being significantly upregulated.

Implications and Future Directions

  • The study provides evidence that targeting MerTK may be a promising strategy for precision therapy in DLBCL patients.
  • Future studies should investigate the mechanisms by which MerTK regulates autophagy and ANXA1 expression in DLBCL cells.
  • Clinical trials are needed to evaluate the safety and efficacy of UNC2025 or other MerTK inhibitors in DLBCL patients.
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