The Proto-Oncogene Mer Is a Novel Therapeutic Target in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is B-cell derived malignant tumor of the hematologic and lymphatic system, which is an incurable disease with most patients eventually relapsing and needing rescue therapy, so new therapeutic targets are emerging quickly nowadays. Mer tyrosine kinase (MerTK) is one of the TAM (Tyro-3, Axl, and MerTK) receptor tyrosine kinase family, and is often overexpressed or ectopic expressed in various malignant tumors, such as melanoma, gastric cancer, leukemia, lung cancer et.al, and is not expressed in normal B or T lymphocytes.

To determine the role of MerTK in MCL, firstly, we analyzed MerTK expression in MCL cell lines by western-blot, and MerTK expression in MCL tumor tissues by Immunohistochemistry (IHC). Three (Z-138, Mino, JVM-2) of 6 (Z-138, Mino, JVM-2, Granta519, JVM-13, JeKo-1) MCL cell lines showed strong MerTK expression. Out of 132 MCL patients, 65 patients (48.9%) showed MerTK expression (positive percentage>10%). The correlation between clinical features and MerTK expression in MCL patients is currently under analysis.

Lentivirus-mediated knockdown of MerTK in Z-138 and Mino cells decreased activation of AKT, ERK 1/2 and P38. Moreover, knockdown of MerTK resulted in inhibition of proliferation and invasion ability in Z-138, Mino and JVM-2 cells, as well as promoted chemosensitization in Z-138 and Mino cells. UNC2250, a MerTK-selective small molecular tyrosine kinase inhibitor, inhibited proliferation and invasion in Z-138, Mino and JVM-2 cells. In cell cycle analysis, UNC2250 induced apparently G2 phase arrest in Z-138, Mino and JVM-2 cells, and also induced polyploidy in JVM-2 cells. Furthermore, western-blot analysis revealed that the G2/M arrest was associated with decrease in pCdc2 and Cyclin B1 protein levels. Meanwhile, UNC2250 showed a dose- and time-dependent apoptotic death in Z-138, Mino and JVM-2 cells, which was associated with increase in Bax, cleaved forms of Caspase 3 and poly (ADP-ribose) polymerase (PARP) protein levels, and decrease in Bcl-2, Mcl-1 and Bcl-xL protein levels. UNC2250 also sensitized Z-138 and Mino cells to treatment with Vincristine and Doxorubicin, which may be a convincing evidence for UNC2250 or other new UNC2250-like MerTK inhibitor being applied in clinical therapy for MCL, allowing for dose reduction in combination with common cytotoxic chemotherapy. Further studies need to be completed in protein assay associated with MerTK inhibition in MCL cells, and the effect of UNC2250 in murine MCL xenograft models are ongoing.

Our data proves that MerTK is highly expressed in MCL patients, and ectopic MerTK expression may be a novel therapeutic target in MCL. Our data also support further pre-clinical or even clinical research about UNC2250 or new MerTK inhibitor.