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Immunoglobulin diversification in B cell malignancies: internal splicing of heavy chain variable region as a by-product of somatic hypermutation
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Immunoglobulin diversification in B cell malignancies: internal splicing of heavy chain variable region as a by-product of somatic hypermutation
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Journal Article
Immunoglobulin diversification in B cell malignancies: internal splicing of heavy chain variable region as a by-product of somatic hypermutation
2002
Overview
In this study we describe alternative splicing of somatically mutated immunoglobulin (Ig) variable heavy chain (V(H)) genes in three distinct primary B cell non-Hodgkin's lymphomas (B-NHL). In two V4-34 expressing lymphomas, ie a post-germinal center type B cell chronic lymphocytic leukemia (B-CLL) and a follicular lymphoma (FL), internally spliced V(H) gene transcripts were found in which a sequence stretch of 116 bp between the framework region 1 (FR1) and complementarity determining region 2 (CDR2) had been deleted. We provide evidence that for this alternative IgV(H) mRNA processing a known cryptic 5' splice donor site and a previously unidentified cryptic 3' splice acceptor site were used. Site-directed mutagenesis showed that the cryptic 3' splice acceptor site had been activated by specific somatic point mutations. The B-CLL further harbored a triplication of the rearranged JH3 gene segment including the putative N region and part of the JH3-JH4 intron sequence. This triplication probably took place via a repeated mechanism of DNA double strand break followed by homologous recombination, a mechanism which was recently proposed also involved in the somatic hypermutation process and is compatible with the post-germinal center derivation of this B-CLL. Finally, in a V4-34 expressing diffuse large B cell lymphoma, we observed alternative IgV(H) mRNA processing using the same cryptic 5' splice donor site and the normal splice acceptor site of the CH1-C(mu) exon. The significance of alternative IgV(H) processing in B cell malignancies and as a potential mechanism of somatic Ig diversification is discussed.
Publisher
Nature Publishing,Nature Publishing Group
Subject
/ Alternative Splicing - genetics
/ Biological and medical sciences
/ Cancer
/ Chains
/ Chronic lymphocytic leukemia
/ Complementarity Determining Regions - genetics
/ Female
/ Genes
/ Hematologic and hematopoietic diseases
/ Homology
/ Humans
/ Immunoglobulin Heavy Chains - genetics
/ Immunoglobulin Variable Region - genetics
/ Leukemia
/ Leukemia, Lymphocytic, Chronic, B-Cell - genetics
/ Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
/ Leukemia, Lymphocytic, Chronic, B-Cell - pathology
/ Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
/ Lymphoma
/ Male
/ Mutation
