AIDS Primary Central Nervous System Lymphoma: Molecular Analysis of the Expressed VH Genes and Possible Implications for Lymphomagenesis (original) (raw)
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Human Immunology, 2000
To investigate the role of somatic Ig hypermutation in the evolution of AIDS-associated B cell lymphomas, we analyzed the Ig V(D)J and c-myc genes expressed by neoplastic B cells in two extranodal sites, testis and orbit, and clonally related cells in the bone marrow. Testis and orbit B cells expressed differentially mutated but collinear V H DJ H , VJ and c-myc gene sequences. Shared mutations accounted for 10.2%, 8.4%, and 4.3% of the overall V H DJ H , VJ, and c-myc gene sequences. Tumor-site specific V H DJ H , VJ, and c-myc mutations were comparable in frequency, and a single point-mutation gave rise to an EcoRI site in the testis c-myc DNA. Both shared and tumor site-specific V H DJ H , VJ, and c-myc mutations displayed predominance of transitions over transversions. The "neoplastic" V H DJ H sequence was expressed by about 10 Ϫ5 cells in the bone marrow, and contained two of the three orbital, but none of the testicular V H DJ H mutations. The nature and distribution of the Ig V(D)J mutations found in the chain suggested a selection by antigen in testis and orbit. Our data suggest that, in AIDS-associated B cell lymphomas, the Ig hypermutation machinery targets V H DJ H , VJ, and c-myc genes with comparable efficiency and modalities.
The American Journal of Pathology, 1999
have recently received considerable clinical attention due to their increasing incidence. To clarify the histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors exhibited clonal IgH gene rearrangements. Of the 10 cases , 5 used the V4 -34 gene segment , and all of these lymphomas shared an amino acid exchange from glycine to aspartate due to a mutation in the first codon of the complementarity-determining region 1. No preferential usage of D H , J H , V , J , V , or J gene segments was observed. All potentially functional rearrangements exhibited somatic mutations. The pattern of somatic mutations indicated selection of the tumor cells (or their precursors) for expression of a functional antibody. Mean mutation frequencies of 13.2% and 8.3% were detected for the heavy and light chains , respectively , thereby exceeding other lymphoma entities. Cloning experiments of three tumors showed ongoing mutation in at least one case. These data suggest that PCNSLs are derived from highly mutated germinal-center B cells. The frequent usage of the V4 -34 gene and the presence of a shared replacement mutation may indicate that the tumor precursors recognized a shared (super) antigen. (Am J Pathol 1999, 155:2077-2086) Supported by the BONFOR program (grant no. 154/27).
Analysis of stepwise genetic changes in an AIDS-related Burkitt's lymphoma
International Journal of Cancer, 2000
In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrangement and sequence and p53 status were analyzed in clones derived from a Burkitt's lymphoma cell line (LAM) in which it was previously demonstrated that Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis. Such evidence was based on the finding that 2 groups of cellular clones, characterized by the same c-myc re-arrangement but different EBV-fused termini, were obtained from the LAM cell line. The Ig V gene sequences were identical for the 2 groups of clones with different EBV-fused termini. The Ig variable heavy (V H ) gene sequence displayed a substantial accumulation of point mutations (but no intraclonal diversification), whereas the productive Ig V lambda (V ) gene sequence was virtually unmutated. Studies on the Ig V kappa (V ) locus suggested a receptor revision event (with a switch from to chain production) prior to EBV infection. Likewise, it was determined that the mutations observed in both p53 alleles and in the re-arranged c-myc gene occurred before EBV infection. Based on these findings, we present a model for the various steps of lymphomagenesis. It is proposed that stimulation by an antigen or a superantigen initially favored the clonal expansion and accumulation of other cytogenetic changes, including those involved in receptor editing. These events occurred prior to or during the germinal center (GC) phase of B-cell maturation. Thereafter, possibly upon exit of the cells from the GC, EBV infection occurred, further promoting lymphomagenesis. Int.
Blood, 1989
Each of three individuals with acquired immunodeficiency syndrome (AIDS) developed a pleomorphic malignant neoplasm in which a precise histopathologic diagnosis could not be rendered. In each case, the tumor cells expressed leukocyte common antigen and a variable constellation of antigens associated with B- and T-cell activation (HLA- DR, T9, T10, BL2, BL3, Ki-24, BLAST-2). They lacked all B cell, T cell, myeloid, and monocyte lineage-restricted antigens, resulting in their classification as hematopoietic neoplasms of uncertain lineage. However, antigen receptor gene rearrangement analysis demonstrated that each of these three neoplasms exhibited clonal immunoglobulin heavy chain and kappa light chain gene rearrangements and lacked T-cell receptor beta chain gene rearrangements and therefore were B cell- derived non-Hodgkin's lymphomas (NHL) representative of an equivalent, relatively mature stage of B-cell differentiation. In contrast with most AIDS-associated NHLs, each of the...
Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma
2003
Aberrant somatic hypermutation in multiple subtypes of http://bloodjournal.hematologylibrary.org/content/102/5/1833.full.html Updated information and services can be found at: (795 articles) Oncogenes and Tumor Suppressors (4217 articles) Neoplasia Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests