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Assessing Somatic Hypermutation in Ramos B Cells after Overexpression or Knockdown of Specific Genes
Published on: November 1, 2011
Antigen receptors and somatic hypermutation in B-cell chronic lymphocytic leukemia with Richter's transformation
Laura A Smit1, Febe van Maldegem, Anton W Langerak
1Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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.
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