Aberrant somatic hypermutation in primary mediastinal large B-cell lymphoma
Davide RossiM CerriDaniela CapelloClara DeambrogiEva BerraSilvia FranceschettiOscar AlabisoAnnunziata GloghiniMarco PaulliAntonino CarboneS. PileriLaura PasqualucciGianluca Gaïdano
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Somatic hypermutation introduces single base changes into the rearranged variable (V) regions of antigen activated B cells at a rate of approximately 1 mutation per kilobase per generation. This is nearly a million-fold higher than the typical mutation rate in a mammalian somatic cell. Rampant mutation at this level could have a devastating effect, but somatic hypermutation is accurately targeted and tightly regulated. Here, we provide an overview of immunoglobulin gene somatic hypermutation; discuss mechanisms of mutation in model organisms that may be relevant to the hypermutation mechanism; and review recent advances toward understanding the possible role(s) of DNA repair, replication, and recombination in this fascinating process.
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In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc.
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Abstract The current model of Ig repertoire development in sheep focuses on the rearrangement of a small number (∼20) of Vλ gene segments. It is believed that this limited combinatorial repertoire is then further diversified through postrearrangement somatic hypermutation. This process has been reported to introduce as many as 110 mutations/1000 nucleotides. In contrast, our data have that indicated somatic hypermutation may diversify the preimmune repertoire to a much lesser extent. We have identified 64 new Vλ gene segments within the rearranged Ig repertoire. As a result, many of the unique nucleotide patterns thought to be the product of somatic hypermutation are actually hard-coded within the germline. We suggest that combinatorial rearrangement makes a much larger contribution, and somatic hypermutation makes a much smaller contribution to the generation of diversity within the sheep Ig repertoire than is currently acknowledged.
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▪ Abstract The relationship between somatic hypermutation and affinity maturation in the mouse is delineated. Recent work on the anatomical and cellular site of this process is surveyed. The molecular characteristics of somatic hypermutation are described in terms of the region mutated and the distinctive patterns of nucleotide changes that are observed. The results of experiments utilizing transgenic mice to find out the minimum cis-acting sequences required to recruit hypermutation are summarized. The hypothesis that V gene sequences have evolved in order to target mutation to certain sites but not others is discussed. The use that different species make of somatic hypermutation to generate either the primary or secondary B cell repertoire is considered. Possible molecular mechanisms for the hypermutation process and future goals of research are outlined.
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