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Abstract
Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL.
Highlights
Primary mediastinal B-cell lymphoma (PMBL) is categorized as a subentity of diffuse large B-cell lymphoma (DLBCL) in the current WHO classification
To determine whether and to what extent Activation-induced cytidine deaminase (AID) is produced in PMBL, we first measured the level of AID mRNA expression in 16 PMBL lymphoma cases along with the PMBL cell lines MedB-1 and Karpas 1106P by quantitative real-time PCR
To relate our measurements to other lymphoma types with known AID expression [12, 31] and to the AID production found in a normal germinal center reaction, we analyzed 15 cases of DLBCL, 11 cases of follicular lymphoma (FL), and microdissected germinal centers of 5 reactive tonsils
Summary
Primary mediastinal B-cell lymphoma (PMBL) is categorized as a subentity of diffuse large B-cell lymphoma (DLBCL) in the current WHO classification. The concept of PMBL as a distinct lymphoma type relies on its characteristic clinical, histomorphologic, immunologic, and molecular properties [1]. The immunoglobulin (Ig) genes of PMBL are clonally rearranged and typically carry a high load of somatic hypermutation (SHM) with a distribution pattern that indicates selection of a functional B-cell receptor [2, 3]. In combination with the finding of switched isotypes [3], this strongly suggests that PMBL originate from B cells that have been exposed to the germinal center reaction. The maturation of a B-cell reaction is achieved by two distinct genetic alterations of the Ig gene. As a hallmark of the germinal center reaction, SHM hones the B-cell receptor for maximum
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