The Differential Expression of Bruton's Tyrosine Kinase in Diffuse Large B Cell Lymphoma and Hodgkin Lymphoma
Zhicheng Mo, Calvin Chen, Randa Alsabeh, Fai Chung, Serhan Alkan. Cedars-Sinai Medical Center, Los Angeles, CA
Background: Bruton's tyrosine kinase (Btk) is a member of the src-related Btk/Tec family of cytoplasmic tyrosine kinases. It plays a critical role in the development and activation of B cells through the B-cell receptor signaling, which regulates cellular proliferation, activation, clonal expansion, and apoptosis of B cells. This kinase is important in B-lymphocyte development and differentiation. The emerging studies suggest that Btk may be a promising therapeutic target for B-cell malignancies. Btk was recently identified as a crucial molecule for survival in a subset of diffuse large B-cell lymphomas (DLBCLs); particularly those identified as non-germinal center type (NGC) type. A clinical trial utilizing an inhibitor (ibrutinib) with anti-Btk activity is initiated. However, expression of Btk in B cell lymphomas had not been investigated.In the current study, we studied Btk expression in reactive lymphoid tissues, DLBCLsand Hodgkin lymphoma.
Design: We performed immunohistochemical study with Btk on 46 DLBCLs including GC type(21/46) and NGC type(25/46). In addition, 15 Hodgkin lymphoma along with 10 benign lymphoid tissues were investigated. Immunostaining was performed with a rabbit monoclonal antibody against Btk as described by the manufacturer. The results were recorded in semiquantitative fashion categorized as negative, weakly positive, or strongly positive cytoplasmic expression in tumor cells. Statistical analysis was done via χ2 analysis. Statistical significance was assumed if p < 0.05.
Results: In all of the benign lymphoid tissues, Btk is strongly positive in mantle zone B cells, and weakly expressed by the germinal center cells. In the cases of DLBCLs, the majority of the cases (42/46, 91%) are positive for Btk expression. The intensity of Btk expression in DLBCLs is heterogeneous. A strong positivity is observed in 28.6% of GC-type and 52% of NGC, respectively (p<0.001). Interestingly, the Reed-Sternberg cells in all the Hodgkin lymphoma cases are negative for Btk expression while few small B-lymphoid cells are noted to be Btk positive.
Conclusions: Our investigation demonstrates that Btk is normally show strong expression in the benign mantle zone B-cells and weakly expressed by the normal germinal center B-cells. The majority of DLBCLs are positive for Btk expression and strong expression of Btk correlates with NGC subtype of DLBCL. Interestingly, about 9% of DLBCLs do not express Btk protein. This result suggests that investigation of Btk expression in DLBCL may be necessary if Btk inhibitor is considered as a therapeutic target.
Monday, March 4, 2013 1:00 PM
Poster Session II # 197, Monday Afternoon