© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 95-100,
1998
© 1998 Oxford University Press
Genetic Basis of Acquired Immunodeficiency Syndrome-Related Lymphomagenesis
* Affiliations of authors: G. Gaidano, Division of Internal Medicine, Department of Medical Sciences, University of Torino at Novara, Italy; A. Carbone, Division of Pathology, I.N.R.C.C.S., Centro di Riferimento Oncologico, Aviano, Italy; R. Dalla-Favera, Division of Oncology, Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, NY
Correspondence to: Riccardo Dalla-Favera, M.D., Division of Oncology, Department of Pathology, College of Physicians & Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032. E-mail: rd10{at}columbia.edu.
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Abstract |
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The molecular pathogenesis of systemic acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL) is a complex process involving both host factors and the accumulation of genetic lesions within the tumor clone. On the basis of the pattern of molecular lesions involved in these tumors, several distinct pathogenetic pathways can be presently identified in AIDS-related lymphomagenesis. These pathways selectively associate with the different clinicopathologic variants of AIDS-NHL. AIDS-related Burkitt's lymphoma is characterized by activation of c-MYC in all cases, disruption of p53 in 60% of the cases, and infection by Epstein-Barr virus (EBV) in 30% of the cases. AIDS-related diffuse large-cell lymphoma harbor frequent EBV infection (80%) and, in 20% of the cases, BCL-6 rearrangements. Finally, the pathogenesis of AIDS-related body cavity-based lymphoma involves infection by human herpesvirus-8 in all cases and frequently also the co-infection by EBV.
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Introduction |
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TopAbstractIntroductionIdentification of Genetic...ConclusionsReferences |
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Non-Hodgkin's lymphoma (NHL) is the second most frequent cancer associated with acquired immunodeficiency syndrome (AIDS) after Kaposi's sarcoma, and in some risk groups, namely, the hemophiliacs, NHL represent the most common AIDS-related neoplasm (1,2). The incidence of AIDS-related NHLs (AIDS-NHL) has continued to rise since the outburst of the AIDS epidemic and, in 1985, the Centers for Disease Control (CDC) has recognized NHL as an AIDS-defining condition (1-3). Because AIDS-NHL are frequently a late complication of AIDS, it is thought that their incidence will continue to increase steadily with the prolongation of life expectancy of human immunodeficiency virus (HIV)-infected individuals (4).
All AIDS-NHL share a number of similarities (2,5). They all derive from B cells, are characterized by extreme clinical aggressiveness, and display a predilection for extranodal sites, including unusual locations otherwise rarely implicated by B-cell NHL of the immunocompetent host. Despite these apparent similarities, however, it is now well established that AIDS-NHL display a marked clinicomorphologic heterogeneity. The detailed pathologic classification of AIDS-NHL has been a matter of controversy and has been recently updated by the World Health Organization (6). First of all, AIDS-NHL may present as a systemic disease (systemic AIDS-NHL) or may originate and locate selectively in the central nervous system (primary central nervous system lymphomas, PCNSL). Depending on histology, AIDS-NHL are generally distinguished into two major categories, which include Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL). AIDS-related BL (AIDS-BL) and AIDS-related DLCL (AIDS-DLCL) account for approximately one third and two thirds of systemic AIDS-NHL, respectively (1). Conversely, AIDS-PCNSL are consistently represented by the DLCL histology. An additional, although rare, pathologic category of AIDS-NHL is constituted by body cavity-based lymphoma (AIDS-BCBL), a peculiar type of lymphoma growing in liquid phase in the serous cavities of the body (7-9).
The pathogenesis of AIDS-NHL is a complex process implicating different phases (2). Initially, factors contributed by the immunocompromised host, and mainly represented by disrupted immunosurveillance and chronic antigen stimulation, lead to polyoligo-clonal B-cell hyperstimulation and hyperplasia, thus configurating the clinicopathologic picture known as persistent generalized lymphadenopathy (PGL) (2,10). The role of disrupted immunosurveillance is exemplified by the close association between low levels of CD4-positive T cells in the host's peripheral blood and increased risk of AIDS-NHL development (11). This association is particularly marked in the case of AIDS-DLCL and AIDS-PCNSL, whereas AIDS-BL may also develop in the context of a relatively preserved immune function. The contribution of chronic antigen stimulation and the selection to AIDS-related lymphomagenesis is documented by the high rate of somatic mutations accumulating in the hypervariable regions of immunoglobulin (Ig) genes expressed by AIDS-NHL cells as well as by the preferential usage of Ig-variable genes belonging to Ig gene families, such as VH4, which are frequently implicated in the generation of B-cell autoreactive clones (12).
Within this context of B-cell hyperstimulation and hyperplasia, the emergence and progressive expansion of the AIDS-NHL clone are driven by the clonal accumulation of genetic lesions within the neoplastic population. The search for these genetic lesions has been the focus of intense efforts during the last 5 years of research in this field. Here we report on the identification of the molecular alterations most frequently associated with the major categories of AIDS-NHL.
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Identification of Genetic Alterations in AIDS-NHL |
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The very first molecular studies performed on AIDS-NHL suggested that the genetic lesions associated with this group of neoplasms are markedly heterogeneous. These same studies demonstrated that, as in other human cancers, genetic lesions of AIDS-NHL may cause different consequences, including the activation of cellular proto-oncogenes, the disruption of tumor suppressor genes, or, alternatively, the insertion of foreign genes in the neoplastic cells, as exemplified by the case of tumor infection by oncogenic viruses.
To define with precision the patterns of genetic lesions associated with the various categories of AIDS-NHL, we have investigated extensively the molecular features of large panels of systemic AIDS-NHL derived from different geographic backgrounds, including the United States and Northern Italy. We have chosen to focus our attention on the genetic lesions most frequently involved in aggressive B-cell NHL of the immunocompetent host, including the alterations of c-MYC and BLC-6 among proto-oncogenes, the inactivation of p53 and 6q among tumor suppressor loci, and the infection by oncogenic herpesviruses.
Viral Infection
Several studies (2,5) have focused on the involvement of EBV in AIDS-NHL. These studies have demonstrated that the virus infects the tumor clone of a large proportion of systemic AIDS-NHL, including 30% AIDS-BL and 70%-80% AIDS-DLCL (13-15). EBV infection is also detectable in 100% AIDS-PCNSL and approximately 90% AIDS-BCBL (7-9,16). In most AIDS-NHL tested, infection by EBV has been demonstrated to be monoclonal, consistent with a model of infection preceding, and putatively contributing to, clonal expansion of the neoplastic population (13,14). Among EBV-positive AIDS-NHL, the expression pattern of the EBV-encoded transforming antigens EBNA-2 and LMP-1 varies substantially (17). Cases of AIDS-BL are consistently negative for expression of both antigens, whereas systemic AIDS-DLCL express LMP-1 in a substantial fraction of cases, approximately 50% (17,18). Some rare cases of systemic AIDS-DLCL also express EBNA-2.
In addition to EBV, another herpesvirus, namely, human
herpesvirus type-8 (HHV-8), is involved in AIDS-NHL pathogenesis,
although at a substantially lower frequency (7-9). Infection of the tumor clone by HHV-8 is
restricted to cases of AIDSBCBL, whereas it is consistently
absent in all other AIDS-NHL types (7-9,19) (Fig. 1, A-C).
Other viruses, including
HIV and HTLV-I, do not appear to be directly implicated in
AIDS-NHL pathogenesis, since they do not infect the tumor clone (2).
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c-MYC
Since the initial phases of the AIDS-NHL epidemic, cytogenetic studies had revealed substantial similarities between AIDS-BL and BL of the immunocompetent host, based on the presence of chromosomal translocations affecting band 8q24, the site of the c-MYC proto-oncogene, and an Ig locus (20). These initial suggestions were later confirmed by molecular analysis of c-MYC in AIDS-NHL samples (14). These genetic studies aimed at defining the frequency and distribution of c-MYC alterations throughout the spectrum of AIDS-NHL and at characterizing the precise mechanism of activation of the proto-oncogene in these tumors. Analysis of large panels of cases have revealed that activation of c-MYC associated selectively with all cases of AIDS-BL, whereas it is absent among AIDS-DLCL and AIDS-BCBL (7-9,14). Although rare cases of AIDSDLCL have been reported to harbor an activated c-MYC, these samples presumably represent cases of AIDS-BL that have been misdiagnosed because of the well-known histologic pleomorphism characteristic of AIDS-NHL (21).
Regarding the precise mechanism of c-MYC activation in AIDS-BL, it generally reflects that typical of sporadic BL, as opposed to endemic BL (14). Thus, in the case of t(8;14)(q24;q32), the most frequent translocation type affecting c-MYC, the translocation breakpoints on chromosome 8 fall within sequences internal or immediately 5' to the c-MYC gene, whereas the chromosome 14 breakpoints map to the Ig switch region (22). As a consequence of the translocation, the expression of the c-MYC gene undergoes transcriptional deregulation (22). In addition to being truncated, the c-MYC gene in AIDS-BL is also frequently mutated within its exon 2 (23). These mutations lead to amino acid substitutions of the c-MYC protein and alter the physiologic interactions between c-MYC and its partner proteins, namely p107 (24). Whereas in normal conditions p107 is able to suppress the transactivation properties of c-MYC, mutated c-MYC alleles are no longer responsive to p107 and thus escape one of the main physiologic mechanisms regulating c-MYC activity (24).
BCL-6
The BCL-6 gene has been originally cloned by virtue of its involvement in chromosomal translocations affecting chromosomal band 3q27 in the DLCL of the immunocompetent host (25). Among NHL of the immunocompetent host, BCL-6 is rearranged in approximately 40% of B-cell DLCL (26). Among AIDS-NHL, rearrangements of BCL-6 cluster selectively with a fraction of AIDS-DLCL, whereas they are absent among AIDS-BL and AIDS-BCBL (27,28). The frequency of BCL-6 rearrangements in AIDS-DLCL is significantly lower than that detected among DLCL of the immunocompetent host, confirming the notion that the pathogenesis of these two groups of neoplasms is different (see also the p53 section below).
Rearrangements involving BCL-6 are promiscuous, in that several distinct chromosomal sites may serve as chromosomal partners juxtaposing to 3q27 (25). In contrast to c-MYC translocations, the chromosomal partners of 3q37 include, but are not restricted to, the Ig loci. The rearrangement breakpoints cluster within a 4-kb region spanning the BCL-6 promoter sequences and the first noncoding exons and result in the fusion of BCL-6 coding sequences (exons 2-10) to heterologous promoters derived from the partner chromosome. This mechanism of BCL-6 alteration is termed promoter substitution and is thought to cause deregulated expression of the BCL-6 protein (29).
In addition to chromosomal rearrangements, the BCL-6 gene in AIDS-NHL may be altered by an alternative type of genetic alteration. Recent studies of NHL of the immunocompetent host have shown that in approximately 70% DLCL and 50% follicular lymphomas the BCL-6 gene is altered by multiple mutations clustering in its 5' noncoding region (30). These mutations frequently occur in the absence of any recognizable chromosomal abnormality affecting band 3q27 or molecular rearrangement of the BCL-6 locus. The genomic sequences most frequently involved by these mutations are adjacent to the BCL-6 promoter region and overlap with the major cluster of chromosomal breakpoints, suggesting that mutations and rearrangements may be selected for their ability to alter the same region. The combined frequency of mutations and rearrangements approaches 100% of DLCL cases arising in the immunocompetent host, suggesting that structural alterations of the 5' noncoding region of the BCL-6 gene are necessary for the development of these tumors (30). To verify the involvement of BCL-6 mutations among AIDS-NHL, we have performed an extensive analysis of this genetic lesion by a combination of PCR-SSCP and DNA direct sequencing in a panel representative of the major pathologic categories of these lymphomas. These data show that mutations of the 5' noncoding regions of BCL-6 are detectable in approximately 60% of systemic AIDS-NHL (28). According to histology, mutations were found to cluster with approximately 70% AIDS-BL and AIDS-DLCL, whereas they were restricted to 20% AIDS-BCBL (28). Within the AIDS-DLCL group, BCL-6 5' mutations occurred both in the presence and in the absence of BCL-6 rearrangements, thus mimicking the pattern reported for DLCL of the immunocompetent host. With respect to other genetic lesions frequently encountered in AIDS-NHL, the presence of BCL-6 5' mutations in a given AIDS-NHL sample was independent of the concomitant presence of c-MYC rearrangements, p53 mutations, and EBV infection (28). The extreme frequency of BCL-6 mutations renders these alterations the most frequent genetic lesion of systemic AIDS-NHL. Since BCL-6 mutations are not only frequent, but are also specific for a given tumor sample, they may be exploited as a molecular marker for monitoring the course of the disease.
In addition to exploring the genetic features of BCL-6 in AIDS-NHL, we have recently investigated the expression status of the BCL-6 protein in these tumors. The BCL-6 protein belongs to the family of transcription factors containing zinc-finger motifs (25). Functional studies have indicated that BCL-6 can function as a transcriptional repressor that can bind a specific DNA sequence and repress transcription from linked promoters (31). Thus, the physiologic function of BCL-6 may be to repress the expression of genes carrying its specific DNA binding motif. Several observations indicate that BCL-6 is involved in the development and function of the germinal center (GC). First, the BCL-6-/- phenotype associates with lack of GC formation, as demonstrated by animal models in which the expression of the physiologic BCL-6 protein has been constitutively abrogated in the germline (32). In addition, since the BCL-6 gene is expressed in GC B cells, but not in their differentiated cell progenies (plasma cells and memory B cells), it is conceivable that BCL-6 may be involved in the induction and sustainment of GC-associated functions and that BCL-6 down-regulation may be necessary for B cells to progress toward further differentiation into memory B cells or plasma cells (33). In NHL carrying a rearranged BCL-6, the down-regulation of the BCL-6 protein may be prevented by the juxtaposition of the gene to heterologous promoters.
Among AIDS-NHL, expression of the BCL-6 protein was found in 100% AIDS-BL and in approximately 50% AIDSDLCL (18). Intriguingly, among AIDS-DLCL, expression of the BCL-6 protein was mutually exclusive with expression of the EBV-encoded antigen LMP-1 (18). The precise molecular mechanism for this phenomenon is presently unclear, although it is interesting to note that BCL-6+/LMP-1- AIDS-DLCL generally display a large noncleaved cell morphology, whereas cases of BCL-6-/LMP-1+ AIDS-DLCL are classifiable as immunoblastic plasmacytoid lymphomas (18). We are currently investigating whether this phenotypic heterogeneity of AIDS-DLCL reflects a different clinical behavior of these two AIDS-DLCL variants.
The concept that LMP-1 and BCL-6 are mutually exclusive antigens
was also based on experimental data derived from the comparison
of the AIDS-BL cell line HBL-2 and its EBV-infected counterpart
HBL-2/EBV. The EBV-negative HBL-2 cell line expresses high levels
of the BCL-6 protein, whereas the cell line HBL-2/EBV, which
expresses LMP-1 in a fraction of cells, exhibits a marked
reduction in the number of BCL-6-positive tumor cells. Notably,
no co-expression of BCL-6 and LMP-1 can be detected in a single
tumor cell of HBL-2/EBV (Fig. 1
, D-F).
The results of genetic and protein studies of BCL-6 may also help us to understand the histogenesis of AIDS-NHL. On one hand, in fact, mutations of BCL-6 5' regulatory regions are generally regarded as a marker of transition of a given B cell through the GC (30). Since a large fraction of these tumors does carry BCL-6 mutations (28), it is conceivable that they derive from B-cell subsets that have already transited through (and potentially reside in) the GC. Furthermore, expression of the BCL-6 protein is also considered as a marker of a B-cell differentiation state corresponding to B cells residing in the GC (33). In this respect, all AIDS-BL and a fraction of AIDSDLCL may thus be derived from GC-proliferating B cells, i.e., the centroblasts (18). According to this same model, the fraction of AIDS-DLCL that do not express BCL-6, but conversely express LMP-1 when EBV infected, may derive from more differentiated B cells that have already exited from the GC (18).
p53
Inactivation of the p53 tumor suppressor gene represents one of the most frequent genetic alterations in human cancers (22). Among B-cell neoplasms of the immunocompetent host, mutations of p53 are virtually restricted to the case of BL and DLCL transformed from a previous follicular phase (22). Inactivation of p53 in human neoplasia most commonly occurs through mutation of one allele and deletion of the other allele, although biallelic deletions, or, alternatively, bi-allelic mutations, may also occur in some cases. In the case of AIDS-NHL, our analysis of more than 50 cases by PCR-SSCP and DNA direct sequencing has demonstrated that p53 inactivation clusters selectively with AIDS-BL, whereas it is consistently absent among cases of AIDS-DLCL and AIDS-BCBL (8,14,28). The pattern of p53 inactivation in AIDS-NHL reflects that of human neoplasia in general. The frequency of p53 mutations among AIDS-BL (60%) far exceeds that of non-AIDS-related BL, including both sporadic and endemic BL (30%) (14). The reason for this excess of p53 mutations in AIDS-BL is presently unknown, although one hypothesis is that it may be related to the host's immunodeficit. Finally, the absence of p53 mutations among AIDSDLCL, combined to the negativity for BCL-2 rearrangements of these tumors, is consistent with the de novo origin of AIDSDLCL. In fact, among DLCL of the immunocompetent host, cases arising de novo are devoid of BCL-2 and p53 lesions, which, conversely, denote cases arising from a preceding follicular lymphoma (22).
6q Deletions
Deletions of the long arm of chromosome 6 (6q) represent a frequent genetic alteration in B-cell NHL of the immunocompetent host (22). Although the relevant tumor suppressor gene is presently unknown, it is thought to map to a small region of chromosomal band 6q27. Among AIDS-NHL, deletions of 6q27 cluster with a fraction of AIDS-DLCL (20%), whereas deletions are consistently absent in other AIDS-NHL types (34). Deletions of 6q27 in AIDS-DLCL may occur in combination with other genetic alterations typical of this lymphoma category, including BCL-6 rearrangements and EBV infection.
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Conclusions |
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The data summarized in this report demonstrate that AIDSNHL is a strikingly heterogeneous disease. At present, four major molecular pathways can be identified. Each of these molecular pathways associates with peculiar clinical features and is restricted to a given AIDS-NHL histologic type. The first pathway associates with AIDS-BL and is characterized by relatively mild immunodeficiency of the host and multiple genetic lesions of the tumor, including activation of c-MYC, disruption of p53, and, although less frequently, infection by EBV. Typically, EBV-infected AIDS-BL fail to express the viral transforming antigens LMP-1 and EBNA-2.
Two distinct pathways associate with AIDS-DLCL, a type of AIDS-NHL generally characterized by a marked disruption of immune function. Whereas the majority of AIDS-DLCL carry EBV infection, only a fraction of cases express the viral antigen LMP-1. Expression of LMP-1 and BCL-6 segregate the two pathways associated with AIDS-DLCL. On the one hand, in fact, LMP-1-positive AIDS-DLCL fail to express the BCL-6 protein and display features consistent with immunoblastic-plasmacytoid differentiation, suggesting a derivation from post-GC cells. On the other hand, LMP-1-negative AIDS-DLCL express BCL-6 and display a large noncleaved cell morphology, suggesting an origin from the GC.
Finally, the fourth pathway associates with AIDS-BCBL. This rare lymphoma type consistently harbors infection by HHV-8 and, frequently, also by EBV. All other genetic lesions commonly detected among AIDS-NHL are consistently negative in AIDS-BCBL.
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Acknowledgments |
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Supported by Public Health Service grant CA37295 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by Ministero della Sanità, Istituto Superiore di Sanità, AIDS project 1997, Rome, Italy; and by Fondazione "Piera, Pietro e Giovanni Ferrero," Alba, Italy.
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