Mutational Analysis of IgV_H and BCL-6 Genes Suggests Thymic B-cells Origin of Mediastinal (Thymic) B-cell Lymphoma

Abstract

Mediastinal (thymic) large B-cell lymphoma (MBL) has been defined as a subtype of diffuse large B-cell lymphoma (DLBL) arising in the mediastinum with characteristic clinicopathological features. It has been postulated that MBL arise from non-circulating thymic B-cells and represent a distinct lymphoma entity, however, the histogenesis of the disease is not yet fully understood. In order to clarify the histogenetic derivation of MBL and to determine the relationship of MBL to thymic B-cells we have analyzed the nucleic acid sequences of immunoglobulin (Ig) heavy chain variable region (VH) and 5' noncoding region of BCL-6 genes in normal thymic B-cells and six cases of MBL. Thymic B-cells and tumor cells of MBLs displayed hypermutated VH and/or BCL-6 genes but intraclonal divergence did not associate with these mutations. Since somatic mutations of the IgVH and BCL-6 genes are histogenetic markers of B-cell transit through the germinal centre (GC), these results suggest that both thymic B-cells and MBLs derived from GC or an equivalent environment where B-cells underwent somatic hypermutation. The similar pattern of mutations of IgVH and BCL-6 genes found in thymic B-cells and MBLs further supports the theory that MBLs originate from thymic B-cells.

POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation

“…Thymus B Cell Lesions in Patz1 Knock-out Mice Are Dependent on Bcl6 Expression-Pathological thymus B cells are considered to originate from the GC (26). Accordingly, focal expression of BCL6 was detected in Patz1-knock-out thymus lesions (either hyperplasia or lymphomas) but was absent in the wild-type controls (Fig.…”

Primary Mediastinal Large B-Cell Lymphoma

“…Despite being primarily a site of T-cell maturation, the thymus does contain a small number of B cells characterized by a unique phenotype showing the presence of CD19, CD20, CD22, and IgM and the absence of CD21 [3]. Hypermutated immunoglobulin heavy chain variable region (IgVH) and bcl-6 genes of a similar pattern have been observed in both PMBCL tumor cells and thymic B cells, supporting derivation from the thymus and suggesting exposure to the germinal center at some point in histogenesis [16].…”

Primary Mediastinal B-Cell Lymphoma

“…Either these cells subsequently migrate to the thymus, or hypermutation may be occurring within the thymus itself outside the classical germinal center. 12,13 Of note, expression of sIg is lost despite the presence of isotype-switched Ig genes.…”