SEARCH:   Advanced

Blood, 15 May 2006, Vol. 107, No. 10, pp. 3818. 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 Müller-Hermelink, H. K. Articles by Rüdiger, T. Search for Related Content PubMed Articles by Müller-Hermelink, H. K. Articles by Rüdiger, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Tam et al, page 4090 Oncogenic pathways in distinct DLBCL subgroups Hans Konrad Müller-Hermelink, and Thomas Rüdiger UNIVERSITY OF WÜRZBURG In this issue of Blood, Tam and colleagues have detected mutations inactivating PRDM1/Blimp-1 in 8 of 35 diffuse large B-cell lymphomas (DLBCLs). PRDM1/Blimp-1 has an important switch function orchestrating plasma-cell differentiation of B cells at the germinal center exit.1 Its chromosomal site, 6q21, is often deleted in diffuse large B-cell lymphoma both of germinal center B-cell (GCB) and activated B-cell (ABC) type.2 According to Tam and colleagues, PRDM1/Blimp-1 occurs in the ABC-type, but not GCB-type DLBCL, as also detected in a parallel paper.3 This inactivation of PRDM-1 suggests that a disturbed terminal B-cell differentiation contributes to the pathogenesis of this type of DLBCL. It is based on the deletion of one allele and mutational inactivation of the other allele or on dominant-negative mutations, classical mechanisms of tumor suppressor gene inactivation. PRDM1/Blimp-1 and BCL-6 mutually inhibit each other at the germinal center exit: BCL-6, expressed in the germinal center, represses PRDM1/Blimp-1, thereby sustaining the germinal center reaction and preventing plasma-cell differentiation. When the balance shifts in favor of Blimp-1, BCL-6 is down-regulated, proliferation ceases, and plasma-cell differentiation is induced.1 Proliferation and differentiation thus occur as subsequent steps, at least in the germinal center reaction. Imbalances in this double-negative feedback balance of BCL-6 and Blimp-1 have now been described for both molecules in DLBCL: BCL-6 may be overexpressed and dysregulated in DLBCL, supposedly of germinal center and post–germinal center differentiation,4 thereby preventing PRDM1/Blimp-1–driven differentiation. PRDM1/Blimp-1 inactivation, in contrast, may be functional in ABC-type, but not GCB-type, DLBCL, because its lack becomes manifest only when the molecule is physiologically up-regulated at the postfollicular differentiation stage. The degree of plasmacytic differentiation and function of genes downstream of PRDM1/Blimp-1 (such as the transcriptional activator XBP1) may indicate the degree of dysregulation and inactivation of this pathway. As a consequence, clear-cut secretory differentiation occurs in only a minority of ABC-type DLBCL. Of interest, the mutual exclusion of proliferation (Ki-67 expression) and PRDM1/Blimp-1–driven differentiation holds true only at the germinal center exit. In the extrafollicular B-cell activation and reactivation of memory cells, proliferating Ki-67+ B cells simultaneously express Blimp-1 and differentiate into plasma cells, suggesting different regulatory mechanisms.5 Thus, the conceptual distinction of germinal-center exit versus memory-cell activation or extrafollicular B-cell activation (based on ongoing somatic hypermutations and immunoglobulin class switch) may allow a further correlation of their specific transformation mechanisms to their physiologic counterparts. References Shaffer AL, Lin KI, Kuo TC, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity. 2002;17: 51-62.[CrossRef][Medline] [Order article via Infotrieve] Bea S, Zettl A, Wright G, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. 2005;106: 3183-3190.[Abstract/Free Full Text] Pasqualucci L, Compagno M, Houldsworth J, et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med. 2006;203: 311-317.[Abstract/Free Full Text] Capello D, Vitolo U, Pasqualucci L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood. 2000;95: 651-659.[Abstract/Free Full Text] Brighenti A, Andrulis M, Geissinger E, Roth S, Müller-Hermelink HK, Rüdiger T. Extrafollicular proliferation of B cells in the absence of follicular hyperplasia: a distinct reaction pattern in lymph nodes correlated with primary or recall type responses. Histopathology. 2005;47: 90-100.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas Wayne Tam, Mario Gomez, Amy Chadburn, Joong W. Lee, Wing C. Chan, and Daniel M. Knowles Blood 2006 107: 4090-4100. [Abstract] [Full Text] [PDF] 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 Müller-Hermelink, H. K. Articles by Rüdiger, T. Search for Related Content PubMed Articles by Müller-Hermelink, H. K. Articles by Rüdiger, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020