Abstract
Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ-resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ-resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ.
Highlights
Mantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin lymphoma
Oerlemans et al reported that BTZ resistance could be acquired by mutations in the proteasome subunit β5 (PSMB5) in BTZ-adapted leukemia cell lines [6], but we did not find a mutation in the PSMB5 subunit in BTZ-resistant cells (Supplementary Figure S1)
To characterize the molecular mechanism regarding how dasatinib inhibits cell viability in BTZ-resistant cells, we investigated the correlation between the p85 subunit of PI3K and CD19, which is activated by the Lyn kinase following B-cell receptor (BCR) signaling activation
Summary
Mantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin lymphoma. MCL is characterized by an aggressive clinical course and a pattern of resistance and relapse with conventional chemotherapy [1]. 30–50% of patients with relapsed MCL achieve remission after bortezomib (BTZ) treatment, more than 50% show innate or acquired resistance to BTZ [1]. Studies of BTZ with other combined regimens have shown that PFS in MCL was limited to 11.5 months [4]. Based on the results of a phase II clinical study, lenalidomide was approved for treatment of relapsed or refractory MCL to BTZ [5]. Lenalidomide combined with cytotoxic regimens was insufficient to achieve PFS, implying that understanding BTZ resistance mechanisms is necessary for the management of MCL patients with disease progression after BTZ treatment. We explored the molecular mechanisms for the BTZ-resistance in MCL with respect to BCR signaling and assessed the efficacy of dasatinib as a therapeutic approach for BTZ-resistant MCL patients
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