Oncogenic pathways in distinct DLBCL subgroups
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《血液学杂志》
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.
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.
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.
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.
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.(Hans Konrad Müller-Hermel)
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.
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.
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.
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.
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.(Hans Konrad Müller-Hermel)