BACKGROUND AND OBJECTIVES: Activation-induced cytidine deaminase is essential for somatic hypermutation and class switch recombination of the immunoglobulin genes in B cells. It has been proposed that aberrant targeting of the somatic hypermutation machinery is instrumental in initiation and progression of B-cell non Hodgkin's lymphomas. In this study, we investigated the B-cell receptor and the role of the somatic hypermutation machinery in B-cell chronic lymphocytic leukemias (B-CLL) prior to and after transformation to a lymphoma of a higher malignancy grade (Richter's transformation). DESIGN AND METHODS: We investigated the activity of the somatic hypermutation machinery in nine B-CLL and secondary diffuse large B-cell lymphomas by measuring the expression of activation-induced cytidine deaminase, in combination with mutation analysis of immunoglobulin (Ig) and non-Ig genes. Furthermore, the structure of the antigen receptors of B-CLL known to have developed a Richter's syndrome (RS B-CLL) was analyzed by comparing the most variable region of the Ig, the CDR3 region, to CDR3 sequences present in GenBank. RESULTS: Ig variable heavy chain (IgV(H)) gene studies revealed that Richter's transformation occurs almost exclusively in unmutated B-CLL. Furthermore, activated-induced cytidine deaminase expression and somatic hypermutation activity of most RS B-CLL were found to be higher than those of control (non-transforming) B-CLL. Finally, comparison of the IgVH-CDR3 regions showed a remarkable amino acid sequence homology between two RS B-CLL of our panel and two RS B-CLL described in the literature. INTERPRETATIONS AND CONCLUSIONS: The combined findings suggest a role for the Ig gene diversification apparatus during Richter's transformation and show that distinct RS-B-CLL may recognize recurrent antigenic epitopes.
BACKGROUND AND OBJECTIVES:Activation-induced cytidine deaminase is essential for somatic hypermutation and class switch recombination of the immunoglobulin genes in B cells. It has been proposed that aberrant targeting of the somatic hypermutation machinery is instrumental in initiation and progression of B-cell non Hodgkin's lymphomas. In this study, we investigated the B-cell receptor and the role of the somatic hypermutation machinery in B-cell chronic lymphocytic leukemias (B-CLL) prior to and after transformation to a lymphoma of a higher malignancy grade (Richter's transformation). DESIGN AND METHODS: We investigated the activity of the somatic hypermutation machinery in nine B-CLL and secondary diffuse large B-cell lymphomas by measuring the expression of activation-induced cytidine deaminase, in combination with mutation analysis of immunoglobulin (Ig) and non-Ig genes. Furthermore, the structure of the antigen receptors of B-CLL known to have developed a Richter's syndrome (RS B-CLL) was analyzed by comparing the most variable region of the Ig, the CDR3 region, to CDR3 sequences present in GenBank. RESULTS: Ig variable heavy chain (IgV(H)) gene studies revealed that Richter's transformation occurs almost exclusively in unmutated B-CLL. Furthermore, activated-induced cytidine deaminase expression and somatic hypermutation activity of most RS B-CLL were found to be higher than those of control (non-transforming) B-CLL. Finally, comparison of the IgVH-CDR3 regions showed a remarkable amino acid sequence homology between two RS B-CLL of our panel and two RS B-CLL described in the literature. INTERPRETATIONS AND CONCLUSIONS: The combined findings suggest a role for the Ig gene diversification apparatus during Richter's transformation and show that distinct RS-B-CLL may recognize recurrent antigenic epitopes.
Authors: Kristina Zaprazna; Kamila Reblova; Veronika Svobodova; Lenka Radova; Vojtech Bystry; Jiri Baloun; Kristina Durechova; Nikola Tom; Tomas Loja; Martina Buresova; Kamila Stranska; Alexandra Oltova; Michael Doubek; Michael L Atchison; Martin Trbusek; Jitka Malcikova; Sarka Pospisilova Journal: Ann Hematol Date: 2018-10-27 Impact factor: 3.673