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What Do Somatic Hypermutation and Class Switch Recombination Teach Us About Chronic Lymphocytic Leukaemia Pathogenesis?

  • Chapter
Chronic Lymphocytic Leukemia

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 294))

Abstract

B-CLL cells express CD5 and IgM/IgD and thus have a mantle zone-like phenotype of naïve cells, which, in normal conditions express unmutated Ig genes. However, recent studies have shown that 50%–70% of CLL harbour somaticmutations of VH genes, as if they had matured in a lymphoid follicle. Interestingly, the presence or absence of somatic hypermutation (SHM) process is associated with the use of particular VH genes. Particular alleles of the VH1–69 gene and the VH4–39 gene are preferentially expressed in an unmutated form, while VH4–34 or the majority of VH3 family genes frequently contain somatic mutations. The fact that some genes like V H 1–69 and V H 3-07 recombine this VH segment to particular JH segments and the restricted use of CDR3 sequences by CLLs expressing the VH4–39 gene suggest that the observed differences in BCR structure in B-CLL could result fromselection by distinct antigenic epitopes. It is currently unclearwhether this putative antigen-driven process could occur prior to leukaemic transformation and/or that the precursors were transformed into leukaemic cells at distinct maturational stages. Themutational profile of Ig genes has been shown to be associated with disease prognosis. These results could favour the idea that CLL could correspond to two different diseases that look alike in morphologic and phenotypic terms. In CLL with mutated Ig genes, the proliferating B cell may have transited through germinal centres, the physiologic site of hypermutation, whereas in CLL with unmutated Ig genes the malignant B cell may derive from a pre-germinal centre naïve B cell. Despite these clinical and molecular differences, recent studies on gene expression profiling of B-CLL cells showed that CLL is characterized by a common gene expression signature that is irrespective of Ig mutational status and differs fromother lymphoid cancers and normal lymphoid subpopulations, suggesting that CLL cases share a commonmechanism of transformation and/or cell of origin. Activation induced cytidine deaminase (AID) plays a key role in SHM and class switch recombination (CSR). However, the mechanisms accounting for AID action and control of its expression remain unclear. In a recent work we have shown that in contrast to normal circulating B-cells, AID transcripts are expressed constitutively in CLL patients undergoing active CSR, but interestingly this expression occurs predominately in unmutated CLL B-cells. These data favour the view that AID proteinmay act differentially on CSR and SHMpathways, but the role-played byAID in both processes remains to be elucidated. Recent work indicates that AID is expressed in a small fraction of tumoral cells, which could suggest that this small fraction of cells may correspond to B-CLL cells that would have recently experienced an AID-inducing stimulus occurring in a specific microenvironment.

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Oppezzo, P., Dighiero, G. (2005). What Do Somatic Hypermutation and Class Switch Recombination Teach Us About Chronic Lymphocytic Leukaemia Pathogenesis?. In: Chronic Lymphocytic Leukemia. Current Topics in Microbiology and Immunology, vol 294. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29933-5_5

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