Bruton Tyrosine Kinase Is Commonly Expressed in Mantle Cell Lymphoma and Its Attenuation by Ibrutinib Induces Apoptosis of Mantle Cell Lymphoma Cells
Munevver Cinar, Farid Saei Hamedani, Zhicheng Mo, Bekir Cinar, Hesham M Amin, Serhan Alkan. Cedars-Sinai Medical Center, Los Angeles, CA; MD Anderson Cancer Center, Houston, TX
Background: The B-cell antigen receptor (BCR) signaling pathway through Bruton tyrosine kinase (BTK) plays an important role in B-cell biology including B-cell malignancies. Therefore, targeted inhibition of BTK is a novel approach for treatment of B-cell malignancies. Increasing body of evidence suggests that blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. The role of BTK in MCL remain elusive. Here, we studied the expression of BTK in human MCL tumors and evaluated the biologic effects of Ibrutinib on well characterized MCL cell lines.
Design: Immunohistochemical analysis of BTK protein was performed in 18 MCLs and 5 reactive lymphoid tissues using an anti-BTK rabbit monoclonal antibody and an automated stainer. Biologic effects of BTK inhibition with Ibritunib was assessed in Mino and JeKo-1 MCL cell lines by exposing to various concentrations and times. MTS or Trypan blue dye exclusion assays were employed to assess cell viability. Flow cytometry using Propidium Iodide (PI) staining was used to determine apoptosis.
Results: Strong expression of BTK was observed in the mantle zone of reactive lymph nodes while weaker staining noted in the germinal centers. A moderate to strong BTK expression was observed in all MCL (18/18). Treatment with Ibrutinib inhibited the viability in a concentration-dependent manner both Mino and JeKo-1 cells and resulted in a concentration-dependent apoptosis. As low as 0.001 µM Ibrutinib significantly reduced the growth of Mino cells; while JeKo-1 cell growth was noted at 1 uM (p<0.01). Ibru
Conclusions: Our results demonstrate that BTK is likely a critical molecule contributing to the survival of MCL, and targeting this pathway appears to be a promising therapeutic modality for a disorder otherwise known to lack an effective treatment. Based on preliminary observation of successful outcomes in currently ongoing clinical trials utilizing BTK inhibitor in various B-cell lymphoproliferative neoplasms including chronic lymphocytic leukemia and subtypes of diffuse large B-cell lymphoma, our results show that targeting BTK pathway in MCL is most likely warranted. Further investigation of BTK biology in MCL is expected to shed more light into understanding the biology of this aggressive type of malignant lymphoma.
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 162, Tuesday Morning