Abstract
BackgroundMantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4–5 years. Mer tyrosine kinase (MerTK) has been reported to be aberrantly expressed in leukemia, melanoma, and gastric cancer, and plays a pivotal role in the process of oncogenesis. This study assessed the role of MerTK in MCL for the first time.MethodsImmunohistochemistry and western blot were performed to figure out expression of MerTK in MCL. MerTK inhibition by either shRNA or treatment with UNC2250 (a MerTK-selective small molecular inhibitor) was conducted in MCL cell lines. MCL-cell-derived xenograft models were established to evaluate the anti-tumor effects of UNC2250 in vivo.ResultsMerTK was ectopically expressed in four of six MCL cell lines. Sixty-five of 132 (48.9%) MCL patients showed positive expression of MerTK. MerTK inhibition by either shRNA or treatment with UNC2250 decreased activation of downstream AKT and p38, inhibited proliferation and invasion in MCL cells, and sensitized MCL cells to treatment with vincristine in vitro and doxorubicin in vitro and in vivo. UNC2250 induced G2/M phase arrest and prompted apoptosis in MCL cells, accompanied by increased expression of Bax, cleaved caspase 3 and poly (ADP-ribose) polymerase, and decreased expression of Bcl-2, Mcl-1 and Bcl-xL. Moreover, UNC2250 delayed disease progression in MCL-cell-derived xenograft models.ConclusionsOur data prove that ectopic MerTK may be a novel therapeutic target in MCL, and further pre-clinical or even clinical studies of UNC2250 or new MerTK inhibitors are essential and of great significance.
Highlights
Mantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4–5 years
Mer tyrosine kinase (MerTK) was ectopically expressed in MCL cell lines and patients’ samples To figure out expression and function of MerTK in MCL, we analyzed MerTK expression in MCL cell lines by western blot and in samples collected from 132 newly diagnosed or relapsed MCL patients by IHC
Western blot showed that normal B cells, JeKo-1, and Granta519 cells did not express MerTK, while Z-138, Mino, JVM-2, and JVM-13 ectopically expressed MerTK at a medium to high level (Fig. 1a), so Z-138, Mino, and JVM-2 cells were selected for further experiments
Summary
Mantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4–5 years. Mer tyrosine kinase (MerTK) has been reported to be aberrantly expressed in leukemia, melanoma, and gastric cancer, and plays a pivotal role in the process of oncogenesis. Mantle cell lymphoma (MCL), an aggressive B cell-derived malignant tumor of the hematological and lymphatic systems, accounts for 6–8% of non-Hodgkin lymphoma [1] and is associated with poor prognosis with a median overall survival (OS) of 4–5 years [2]. As in other RTK family proteins, aberrant expression of MerTK in various malignant tumors, such as melanoma [12, 13], gastric cancer [14], leukemia [15,16,17], and lung cancer [18], plays a pivotal role in the process of oncogenesis. Ectopic MerTK may be a pivotal promoter in the development of B or T cellderived hematopoietic malignant tumors
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