SEARCH:   Advanced

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chiorazzi, N. Search for Related Content PubMed Articles by Chiorazzi, N. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2003, Vol. 102, No. 5, pp. 1564-1565 Aberrant somatic hypermutation and lymphomagenesis Many non-Hodgkin lymphomas (NHLs) arise from B lymphocytes with chromosomal translocations that result in constitutive activation of oncogenes. In certain cases of NHL, mutations occur in regulatory regions of proto-oncogenes, and these may represent another mechanism for oncogene deregulation, independent of translocation. This latter process was first described in a subset of patients with diffuse large B-cell lymphoma (DLBCL; Pasqualucci et al, Nature. 2001;412:341-346). The characteristics of the mutations (eg, location on the chromosome and nucleotides affected) in these DLBCL cases resemble those found in the IgV and BCL-6 genes of normal germinal center (GC) B lymphocytes undergoing the somatic hypermutation (SHM) process and are consistent with the derivation of some DLBCLs from GC B cells (Alizedah et al, Nature. 2000;403:503-511). However, since these proto-oncogenes are not mutated in normal GC B cells, a mistargeting of the SHM process during the GC reaction, "aberrant somatic hypermutation," was invoked as a cause for these potentially dangerous gene alterations in immunocompetent patients with DLBCL (Pasqualucci et al). In this issue, Gaidano and colleagues (page 1833) report similar somatic gene changes (mainly point mutations with infrequent nucleotide deletions or insertions) in regulatory and occasionally coding regions of several proto-oncogenes of NHL cells from patients with AIDS. They describe clonal abnormalities in one of these genes in approximately 50% of cases and in two genes in approximately 25% of patients. The point mutations identified had characteristics consistent with those occurring during SHM and similar to those previously defined in patients with DLBCL and intact immune systems. Thus, mistargeting of the adaptive SHM mechanism appears to represent a general phenomenon leading to clonal deregulation and lymphoma. Since these clonal abnormalities may have a broader spectrum than those initially reported in NHL patients without AIDS, this maladaptive process may be even more common in the setting of immune compromise. The SHM process involves expression of the activation-induced cytidine deaminase gene, which is necessary and sufficient for this process (Muramatsu et al, Cell. 2000; 102:553-563). Although not analyzed in the studies of Gaidano et al, others recently reported the expression of activation-induced cytidine deaminase in NHL (Greeve et al, Blood. 2003;101:3574-3580). SHM and activation-induced cytidine deaminase may be linked to lymphomagenesis by generating double-strand DNA (dsDNA) breaks, which could initiate chromosomal translocations (Kuppers and Dalla-Favera, Oncogene. 2001;20:5580-5594) and the mistargeted and dangerous mutations described by Gaidano et al and Pasqualucci et al. Thus, the seminal observations of the Dalla-Favera laboratory implicate aberrant targeting of the SHM process in the initiation of several aggressive B-cell lymphomas. Since the occurrence, over time, of new mutations in the same proto-oncogenes was occasionally identified, this mistargeting may also lead to the accumulation of additional genetic lesions and to the evolution of even more aggressive disease. If so, the SHM process and activation-induced cytidine deaminase may be therapeutic targets to limit lymphoma progression. Nicholas Chiorazzi North Shore-LIJ Research Institute, North Shore University Hospital, and New York University CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chiorazzi, N. Search for Related Content PubMed Articles by Chiorazzi, N. Social Bookmarking                   What's this?

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020