pathogenetic mechanisms in b-cell non-hodgkin's lymphomas ... · pathogenetic mechanisms in...

(CANCER RESEARCH (SUPPL.) 52, 5522s-5528s, October 1, 1992)

Pathogenetic Mechanisms in B-Cell Non-Hodgkin's Lymphomas in Humans1

Michael Potter2

Laboratory of Genetics, Division of Cancer Biology and Diagnosis, National Cancer Institute, NIH, Betfiesda, Maryland 20892

Abstract

A very large proportion of non-Hodgkin's lymphoma in the United

States are of B-cell origin. This group of tumors includes a variety ofdifferent pathological and clinical types. Chromosomal rearrangementsplay an important role in the pathogenesis of many of these tumors. InB-cells these translocation processes appear to develop as illegitimateproducts of physiological V-(D)-J or heavy chain switch rearrangements. The biology of the well-known chromosomal translocations isdiscussed. Additional biological factors in lymphomagenesis (aging, immunodeficiency, role of antigenic stimulation, and genetically determined susceptibility) are discussed.

Introduction

This paper is an introduction to the discussion of the biologyof NHLs1 and will attempt to outline some of the important

issues. The NHL group of tumors includes a heterogeneousgroup of morphological and physiological entities (1, 2). Twodifferent cell lineages, T- and B-lymphocytic forms, are included in most listings. Although T- and B-lymphocytes arederived from the same stem cells, they develop differently andhave different functions in immune responses and probablyshould be considered separately in epidemiological studies. TheB-NHLs comprise over 80% of NHLs in the United States (3)and furthermore are the predominant type of NHL associatedwith the increased incidence of NHLs that has occurred in thelast few decades in the United States. Epidemiologists usuallyconsider other lineage-related B-cell tumors such as the B-cellleukemias and Ig-secreting plasma cell tumors separately fromthe B-NHLs, even though tumors such as chronic B-cell leukemias and multiple myeloma are closely related biologically. Onebasis for this distinction is that the incidence of B-NHL appearsto change in certain populations independently of other B-cell

tumors (4, 5).The increased incidence of B-NHLs and multiple myeloma

over the last few decades coupled with the number of othervarieties of B-cell tumors provides strong evidence that the cellsof the B-cell lineage comprise one of the more vulnerable targettissues in the human body for neoplastic development. Theincreased incidence of B-NHLs appears to affect many if not allof the entities in the Working Formulation (1). There weresome indications of specificity. Devesa and Fears (4) noted adecline in low-grade follicular small cleaved cell and intermediate-grade diffuse small cleaved cell lymphomas. The intermediate-grade diffuse large cell lymphoma increased the most dramatically (4). Interestingly, these tumors formed a prominentgroup in persons exposed to herbicides (6). Diffuse large celllymphomas are heterogeneous by immunophenotyping, andthere is little cytogenetic or molecular information available onthese tumors. Since these may represent a chemically inducedB-NHL it will be of interest to obtain new information on this

1 Presented at the National Cancer Institute Workshop, "The Emerging Epidemic of Non-Hodgkin's Lymphoma: Current Knowledge Regarding EtiologicalFactors." October 22-23, 1991, Bethesda, MD.

2 To whom requests for reprints should be addressed, at Laboratory of Genetics,Division of Cancer Biology and Diagnosis, National Cancer Institute, Building 37,2B04, Bethesda, MD 20892.3 The abbreviations used are: B-NHL. B-cell non-Hodgkin's lymphoma; IL,interleukin; MACTR, Myc-associated chromosomal translocalions and rearrangements; HIV, human immunodeficiency virus; EBV, Epstein-Barr virus.

type of B-NHL. An increased incidence of high-grade blasticlymphomas associated with HIV infection will also change thedistribution of lymphoma types in the near future.

B-Cell Non-Hodgkin's Lymphomas

The cells of B-NHLs are lymphoblasts or lymphocytes withdifferent morphologies that characteristically express membrane-associated Ig molecules which function as antigen receptors (3). Some may secrete Ig, but for the most part the cells donot acquire an extensive rough endoplasmic reticulum, and Igsecretion, when observed, is usually limited. B-NHL cells arerelated to B-cells that have completed V-(D)-J Ig-gene rearrangements in the bone marrow but which have not maturedinto Ig-secreting plasma cells.

The B-NHLs are distinguished biologically from other B-celltumors by their proclivity for proliferating in secondary lym-phoid organs, i.e., lymph nodes, spleen, and mucosa-associatedlymphoid tissue and less well understood extranodal sites. Lymphoma cells can also be found in the peripheral blood (7) andsecondarily in the bone marrow. Although some lymphomasmay have an apparent focal origin in lymph nodes or in extra-nodal sites, others involve multiple nodes at the time of discovery. This is probably due to the spread of lymphoma cellsthrough the circulation and preferential homing into other lymphoid tissues, characteristics not unexpected from the normalrecirculation of B-lymphocytes.

In the discussion to follow on pathogenesis the B-NHLs aredivided into two biological groups (Table 1). Group I consists oflymphomas that retain some of the special differentiation phe-notypes of B-cells: somatic hypermutation; heavy chain switching; continuous circulation and recirculation; localization tospecific regions in lymphoid tissue; the formation of follicle-likestructures; and the tendency to have many cells in the tumor inthe GO stage of the cell cycle. These lymphomas are in generalthe more chronic low- and intermediate-grade tumors in thecurrent classifications. B-cell chronic lymphocytic leukemiashould be included in this group because of the many closebiological relationships with certain B-NHLs, but it is nonetheless reported as a separate epidemiological entity. Group Ilymphomas can appear in any age group but most commonlybecome manifest in later life. Group II lymphomas are thehigh-grade blastic tumors that often grow explosively. Thesetumors are more common in younger age groups. Some of thesetumors may be polyclonal. The pathogenetic mechanisms to bedescribed have been developed for some but by no means all ofthe B-NHLs. The grouping of B-NHLs used here is very oversimplified for purposes of discussion and is not intended to beanother classification.

Pathogenetic Factors Relevant to the EpidemiologicalProblem of Increased Incidence of B-NHL

Chromosomal Rearrangements. Illegitimate chromosomalrearrangement is an important mutational mechanism in manyB-NHLs. Understanding the underlying mechanisms that contribute to this process is relevant to the current epidemiologicaldiscussion. Little is known about agents that influence abnormal chromosomal rearrangements, but at this meeting Kirsch

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PATHOGENETIC MECHANISMS IN B-CELL NON-HODGKIN'S LYMPHOMAS

Table 1 Differences in two groups of B-cell NHLs

Characteristic Group I Group II

Histology

Cell types

Clinical

Progression

Median age

Extranodal

EBV

ImmunophenotypeAdhesion molecules

Chromosomal

Oncogenes

Diffuse

Small noncleavedAtypical large lymphoblasts

Endemic Burkitt'sSporadic Burkitt'sAIDS-associated"

Lymphomas in hereditary immunodeficiency

Usually rapid

17-30 years

Jaw tumors (eBL)CNS, GI tract

Frequently positive

LFA-pl50/95(CDllc)-CD44-

t(8;14)t(2;8)(8;22)

C-mycPvi-l

Nodular of follicularSome diffuse

Small cleavedLarge cleaved

Follicular lymphomaCentrocytic (mantle zone) lymphoma or intermediateLymphocytic lymphoma

Often indolent, slow

51-60 years

Salivary' glands in Sjogren's syndrome

t(14;18)HI 1:1411(10:14)Other 14q32

BCL-2BCL-I

' AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; GI, gastrointestinal.

has provided evidence that occupational exposures to pesticidescan increase the rate of formation of illegitimate recombinations [e.g., inv (7)pl3;q35)] between T-cell receptor genes.While this inversion is not associated with the activation ofan oncogene, it suggests that exogenous factors can affect re-combinational processes in cells. Garry et al. (8) have describedchromosomal rearrangements, including stable translocationsin fumigant applicators exposed to phosphine. These observations open up a new line of investigation applicable to thepathogenesis of B-NHLs. For the first time it should be possibleto identify agents in the environment that modify the rate offormation of illegitimate recombinations and investigate thebiochemical basis for their formation. This would appear toprovide an important avenue for epidemiological investigation,i.e., to identify agents in the environment that increase illegitimate exchanges, particularly in B-cells.

The Ig genes in B-cells (and T-cell reactivity genes in T-cells)undergo extensive structural changes during normal development. There are two separate rearrangement processes: V-(D)-Jrearrangements that occur during the early pro-B/pre-B stagesand heavy chain isotype switching that takes place in matureperipheral B-cells. In each process DNA is broken and rejoined;different enzymes are probably involved in the two processes.The V-(D)-J gene rearranging steps involve Ig genes in threedifferent chromosomal loci: DH-*JH, VH^DHJH on chromosome (chr) 14; VKâ€”JK on chromosome 2; and VX^JX onchromosome 22. In all three of these rearrangements distant asIg gene elements are brought together or aligned prior to thescission and ligation. The complexities of the cellular stepsassociated with these rearrangements have been recently reviewed (9). The important end result of gene rearrangement isthe formation of a vast number of exquisitely specialized clono-types, each of which is limited to making only a single type ofIg molecule.

Ig heavy chain switching is a more general process and probably occurs whenever B-blasts are activated into the cell cycle by

antigen or nonspecific polyclonal activators such as lipopoly-saccharide (see Ref. 10). Switching takes place in several different sites (primary lymphoid follicles, T-rich zones) in thespleen, lymph nodes, and mucosa-associated lymphoid tissue(11). Cytokines such as IL-4, IL-5,7-interferon, and transforming growth factor ÃŸtrigger through signal transduction pathways nuclear factors that act on specific DNA switch regions,causing them to assume an open configuration that is a prerequisite for recombination (see Ref. 10).

The V-(D)-J rearrangements and heavy chain switching playan important role in B-cell lymphomagenesis because duringthese processes Ig genes are opened up and the double-strandedDNA is broken and rejoined. This makes open ends of Ig DNAavailable not only for the normal rejoining process but also forillegitimate exchanges. The activity of recombinational machinery is restricted to specific stages of B-cell development (12),and this makes it possible to associate translocations involving:(a) a JH gene with the pro-B period and DHâ€”-JHjoining; (b) Jkand JX genes with the pre-B period; and (c) switch regions withantigen-activated stages. These associations establish the B-cellspecificity of translocations. The t(14;I8)q32q21 which activates bcl-2 and t(8;14)q24;q32 which activates c-myc are themost common reciprocal translocations in B-NHLs. There areother less common but recurring 14q32-associated translocations: (a) t(ll;14) ql3;q32, in which bcl-1 (13, 14) is activated;(b) t(10;14)q24;q32, in which lytlO is the target gene (15); and(c) t(14;19) 14q32;q23, in which bct-3 is the target gene (16).

One putative mechanism for double-stranded DNA breaks inthe Ig chromosomal partner is attributed to physiological re-combinases. An alternative is that the breaks in the Ig chromosome are caused by other agents that nonspecifically cut theaccessible DNA. The cause of the breaks in the non-Ig chromosomal partner is not established. The explanations offeredare somewhat controversial. One school of thinking proposesthat these are generated by the recombinases themselves thatmistakenly recognize signal-like sequences (17) or sequences

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that are "tantalizingly like switch recombination sites" (18) in

the target gene. Tycko and Sklar (19) have recently reviewed allof these examples and found that the ectopie recombinationsignals were highly variable and that many were not closematches for heptamer-spacer-nonamer signals. They concludedthat the recombinases may generate breaks in the Ig gene-bearing chromosome but that the breakage events in the target geneswere random and probably not site specific. Evidence frommolecular analysis of reciprocal break points has shown that thenon-Ig breaks are staggered scissions occurring in both strands(18, 20) raising the possibility that other factors such as thosetriggered by oxidative damage (21) might contribute to chromosomal breakage in both the Ig and non-Ig chromosomes.

Why certain non-Ig genes are selected as "illegitimate" part

ners in translocations with Ig genes is not yet understood. Theremay be several contributing factors. First the target (non-Ig)gene may be coincidentally transcribed or synthesized duringthe Ig gene rearrangement process. Second, the expression ofthat target gene provides a survival advantage for the B-cell inwhich it occurs. It seems clear that the non-Ig target gene mustbe in close proximity to the rearranging Ig gene complex topermit recombination. One mechanism for bringing togethergenes on different chromosomes is that during DNA synthesis,replication units including polymerases are fixed on the nuclearscaffold. Such complexes form sites where from 300 to 1000replication forks are located in one unit (22). If loops of chro-matin from different chromosomes occupy one of these sites theeliminatili could be positioned for recombination during DNAsynthesis or transcription.

Illegitimate recombinations usually disrupt regulatory sequences of the non-Ig gene, resulting in activations and dysreg-ulation of the transcription or translation of the gene. It hasbeen speculated that dysregulation of target genes might provide survival advantage to the cell. If this is so, evidence ofclonal expansion of the mutant clone should occur. The phenomenon of clonal stem cell expansion has been observed forthe Â¿>(T-flA/-associatedt(9;22) [Philadelphia] translocations inchronic myelogenous leukemia and some B-cell acute lympho-cytic leukemias (23). In a mature B-cell it may be more difficultfor a clone to expand in the periphery and displace other clones.A brief discussion of two common kinds of translocations inB-cell lymphomas, the t(14;18) that activates bcl-2 in follicularlymphomas and the Myc-associated chromosomal rearrangements (MACTRs) that result in c-myc, provide further insights

into this process.In t(14;18) a break site in JH on chromosome 14 is joined to

bcl-2 on chromosome 18 (20, 24, 25). The involvement of theJH breaksite in i( 14:18) has suggested that the translocationtakes place in the pro-B period of B-cell development when DHrearranges to JH and the JH region is accessible. During thisperiod the Ig gene-specific recombinases (12) as well as terminal deoxytransferase are active. The breaks occur in the 5' end

of the JH region, which suggests a potential role for immuno-globulin rearranging recombinases in this step (19). However,the detailed molecular analysis of the break sites has revealedstaggered double-stranded breaks in chromosome 18 in sometumors (20), while in others sequences resembling heptamer-nonamer have been described near the break sites (17). There isdisagreement on whether the heptamer-nonamer-like signal sequences in the bcl-2 gene are able to signal the recombinases(19). It is possible the break in chromosome 18 may be induced, by DNA-damaging agents rather than by physiologicalrecombinases.

The t(14;18)-carrying cell overexpresses bcl-2 protein(23, 26-28) from its putative time of inception in the pro-Bperiod. Since a major physiological effect of bcl-2 overexpres-sion is to prevent apoptosis and prolong the life of a cell (29,30), clonal cells carrying this mutation may be able to expand inthe pre-B period or even later; however, the abnormal prolifer-ative phenotype is not expressed until the cell becomes a matureB-cell.

Several pieces of evidence suggest that the t(14;18) translocation does not render the cell tumorigenic. First, Limpens etal. (31) have detected t(14;18) translocations in nonneoplastichuman tonsil tissues. Second, in a remarkably high number ofcases studied (7 of 44), evidence of two different t(14;18)s hasbeen found in the same case (32). This implies that the t(14;18)may occur far more frequently than the incidence of lymphomasreflects. An implication of these findings is that t( 14; 1Si-carrying cells are generated in many persons in the course of alifetime, but the cells are either eliminated or never progress tobecome tumors. This important possibility must await furtherconfirmation. The persistence of cells bearing the t(14;18)translocation during the remission of follicular lymphoma (33)also raises the possibility that these t(14;18)-bearing cells are

not part of the tumor population but are precursors from whichthe tumor was derived. Possibly, then, certain factors or environmental conditions could favor the survival of t( 14; 18) cellsand stimulate the progression toward greater proliferativeautonomy.

The bcl-2 gene codes for a A/r 25,000 protein that surpris

ingly is located on the inner surface of mitochondrial membranes (23). The biochemical mode of action of the gene product is not known, but excessive production of bcl-2 productblocks apoptosis and extends the life of the B-cell (24). The bestdocumented example of apoptosis in B-cells occurs in second

ary follicles (34, 35). As centroblasts emerge from these rapiddivisions they reexpress Ig molecules that function as antigenreceptors. They are then exposed to antigen that has been released from follicular dendritic cells. Those cells that fail tobind to their respective antigen undergo programmed cell death(apoptosis) (34, 35). Centrocytes that do bind antigen can eithergo on to become Ig-secreting cells (plasmablasts) or memorycells. Survival is influenced by the availability of soluble A/r25,000 CD23 (released from follicular dendritic cells) and IL-la, which promote differentiation to plasma cells, or the CD40ligand that promotes differentiation into memory B-lympho-cytes (35). Cells which express large amounts of bcl-2 productwould be able to remain viable even though they do not respondto antigen. 11\pol helically this could result in salvaging centro-cytes that have not been selected by antigen (including centro-cytes that could react with self-antigens). These cells stimulatedby other factors might then proliferate.

Transgenic strains of mice have been constructed that carrybcl-2 (36-38) under the control of unnatural regulatory influences such as the Ig heavy chain enhancer (Eu-bcl-2) (49) or thebcl-2-lg fusion gene (38). These mice make it possible to observe the pathophysiological effects of overexpression of bcl-2.

Overexpression of bcl-2 in the B-cell lineage produces several

striking immunological effects (30, 36, 38, 39). First there wasa 3- to 4-fold expansion of small resting (u+ d+, CD5~, poten

tially lipopolysaccharide responsive) B-cells in the spleen lymphnodes and bone marrow. Secondary immune responses in theEu-bcl-2 transgenic mice are also greatly exaggerated and prolonged for many days (36). In the bcl-2-lg transgenics both

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memory B-cells and Ig-secreting cell compartments are expanded; and memory B-cells which usually have a short duration in normal individuals persist for long periods in thesetransgenics (38). Pathologically enforced bcl-2 expression inEu-bcl-2 transgenic mice can induce autoimmune disease (36);

furthermore, a few of these mice after long latent periods develop plasmacytomas (40). After a long latent period mice carrying the bcl-2-lg transgene develop diffuse large cell immuno-blastic lymphomas; a number of these have a rearrangement ofc-myc (39).

The chromosomal translocations that activate c-myc (MAC-TRs) are t(8;14)q24;q32, t(2;8)pl2;q24, and t(8;22)q24;qll.MACTRs are found in nearly 100% of endemic and sporadicforms of Burkitt lymphomas, in a high percentage of acquiredimmunodeficiency syndrome-associated lymphomas (41), andin other lymphomas arising in immunocompromised individuals (42). In many of these conditions the incidence of MACTRsis high and approaches 100% as in the Burkitt lymphomas,indicating the importance of these translocations and the activation of c-myc in the pathogenesis of these lymphomas.

The relevant physiological functions of the c-myc gene arenot yet understood. Only recently has it been shown that theprotein product of the c-myc dimerizes with the product of themax gene to form a specific DNA-binding protein (43). Although c-myc transcription occurs throughout the active cell

cycle (G] to M), it undergoes a burst about l h after the cellsmove from G0 to G! and then attains a lower but sustainedtranscription throughout G, until mitosis (44). c-myc is nolonger transcribed when the cell goes out of cycle as in theterminal differentiation of HL-60, several erythroleukemiccells, and 3T3-L1 pre-adipocyte lines (see Ref. 44). For severalreasons it is thought that c-myc may be a transcriptional regulator (45) that is essential to committing the cell to a programof DNA synthesis and mitosis. Since c-myc probably actsthroughout the GÃŒphase it may regulate several other functionsrelating to the progression through this part of the cycle. Possibly some of these permit cells to respond to exogenous growthor progression factors, c-myc down-regulation is an apparentrequirement for terminal differentiation in other non-B-celltypes; this is probably true for B-cells as well, c-myc dysregula-

tion may serve to maintain cells in a proliferative cycling mode,but more critically for B-cells, it may block the ability of B-cells

to enter a G0 state (45).

Aging. Aging is probably an important contributing factor inthe pathogenesis of the Group I B-NHLs, since these tumors

occur predominantly in older age groups, and the increase inthe rates rose in each age group over 55 years (4). The underlying biological explanation for how aging influences lymphom-agenesis is not yet well understood. The effect of aging on theimmune system has been studied for a number of years. Theconcept that aging is an immunodeficient state may be toogeneral a statement (46). A number of individual immunolog-ical deficits are now documented, but many components ofimmune responses are intact (46-50). New clonotypes may beexpressed in the bone marrow (47). The net result as suggestedby Russo et al. (46) is a dysregulation of the immune system.

First, it is well known that the thymus involutes and thus theT-cell repertoire depends more heavily on the peripheral pool.In addition, T-cell proliferation (48) and IL-2 production decrease (46). Autoreactive T-cells appear with increasing age(46). There is a striking reduction in older persons in the phy-tohemagglutinin responsiveness of peripheral blood T-cells,

which are reduced to 30% of those seen in young subjects (48).The underlying mechanism is not yet clear, but Beckman et al.(48) have provided evidence that T-cells from elderly individu

als are capable of responding to mitogens when artificially provided in vitro but that in vivo there is a defect in the ability of theT-cells to interact with accessory cells.

In the B-cell lineage humoral responses to foreign antigensdecrease while production of autoreactive antibodies increases(46). Changes in the B-cell repertoires in mice occur with agingthat may change V,D,J gene selection (47). Human B-cells from

old individuals proliferate 50% less efficiently than those fromyoung subjects; these differences may be due to impairments incomponents of certain signal transduction pathways in B-cells(49, 50). Other deficits have been described in mice, including adefect in antigen transport and germinal center formation in oldmice (51). Finally, it has long been known that the incidenceof monoclonal gammopathies of undetermined significanceincrease dramatically with age (52). The formation of theselesions has been linked to some form of age-related T-cell im

munodeficiency that can be augmented nonspecifically by intercurrent illness (52).

Thus aging is associated with imbalances in T- and B-reper-

toires. The regulation of the size and proliferative activities ofcertain B-cell clonotypes in older individuals may be less wellcontrolled because of the changes in the T-cell compartment.This, coupled with the increased frequency of autoreactiveclonotypes, may produce a population of B-cells that is lesssubject to regulation by T-cells and which is at increased risk forfurther progress toward autonomous growth.

This raises epidemiolÃ³gica! questions. Assuming there arepotential lymphomagenic agents in the environment such as theherbicides and pesticides (6, 53), how would such exposuresinfluence the incidence rates in various age groups? Would suchagents affect all or only the older age groups? If as the verypreliminary available data indicate the rate changes are predominantly in the older age group, one would then argue thatthe B-cells in older subjects are at greater increased risk ofundergoing neoplastic transformation than B-cells fromyounger subjects.

Immunodeficiency. B-cell lymphomas (Group II) are associ

ated with different forms of immunodeficiency. Lymphomashave appeared in an alarmingly high incidence in HIV-infectedindividuals (54, 55); these have sometimes occurred as thepresenting manifestation of the disease. Most frequently thelymphomas develop in the immunodeficient state. Secondarylymphomas develop in relatively high frequency in genetic immunodeficiencies such as the Wiscott-Aldrich syndrome, ataxiatelangiectasia (56), and other X-linked immunodeficiencies(57). Lymphomas are a well-known complication in posttransplantation immunosuppression by drugs (58, 59). Some ofthese lymphomas regress after withdrawal of the immunosup-pressive drug (59). B-NHLs associated with immunodeficiency

states are frequently oligoclonal or polyclonal, and this hasraised the issue that some of these lymphomas represent lym-phoproliferative rather than neoplastic disorders. Many of thelymphomas arising in the various forms of immunodeficiencyare EBV+, suggesting the participatory role of EBV genes in the

lymphomagenic process. The basic mechanism for lymphoma-genesis in immunodeficiency is thought to involve a breakdownof immunological surveillance and the ability of T-cells to eliminate cells expressing atypical cell surface antigens.

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EBV is associated with many of the Group II lymphomas;virtually 100% of endemic Burkitt lymphomas are EBV-posi-tive, but a much lower frequency is seen in sporadic Burkittlymphomas. The frequency varies in acquired immunodeficiency syndrome-associated NHLs and NHLs in other immu-

nodeficient states. EBV is a ubiquitous viral infection in humans, and over 95% of adults are persistently infected (60). Indeveloping countries virtually all children by the age of 3 havebeen infected (61). However, the virus does not produce obviousdisease but does persist indefinitely. Viral persistence is maintained in two tissues, the nasopharangeal epithelium and B-

cells, but details of the mechanism are not yet established (60).In Hcells the virus is maintained as a plasmid in the cytoplasmof resting cells. A substantial number of B-cells are infected.Newly infected (nonneoplastic) B-cells and the immortalized

lymphoblastoid cell lines that can be cultured from the blood ofpersistently infected individuals express multiple viral proteinsEBNAs 1, 2a, 3a, 3b, 3c and EBNA-LP, LMP1, 2A, 2B butproduce very little virus (60). These cells actively proliferate;however, their EBV-associated membrane proteins can be an-tigenic targets for cytotoxic T-cells. In normal individuals EBVproduction is held in check by active cellular and humoral immune mechanisms. Three different EBV-B-cell relationshipsthat are associated with EBV latency have been recently described (60). In immunodeficient states this balance can be disrupted, and EBV-infected B-cells can begin to proliferate. Interestingly, Burkitt lymphoma cells express only EBNA-1 andtherefore appear to escape immunological surveillance.

EBV many contribute to immortalization and growth dysreg-ulation through the action of some of its genes on the B-cellgenome. EBV infection is associated with changes in B-cellproliferative behavior. It has long been known that immortalized B-cell lines can be relatively easily established in vitro fromthe peripheral blood cells of persistently infected individuals. Inrecent rather dramatic studies Mosier et al. (62) and Rowe et al.(63) have shown that transplantation of peripheral blood cellsfrom normal healthy persons with persistent EBV to severecombined immunodeficiency disease mice results in the development of transplantable lymphomas that kill their hosts. EBVgenes then can contribute to abnormal B-cell growth and au

tonomy as defined by this system. It is a startling thought thatmost of us have cells in our blood with the potential for suchabnormal growth.

Role of Antigenic Stimulation. Sustained or intense antigenicstimulation provided by the excessive production of antigensmay play an important role in lymphoproliferation and in somegroup II lymphomas. Malaria and HIV infections are thoughtto not only provide intense antigenic stimulation but also toact as a continuing source of new antigens arising from antigenic variation of the infecting agent (61,64). Both Malaria andHIV infections are associated with B-cell lymphoproliferation,which may be due to both specific antigens generated by theinfectious agent and nonspecific mitogenic effects. Interestingly, both of these infections are associated with the formationof a relatively high number of extranodal lymphomas.

The role of antigenic stimulation in the Group I lymphomasis less well defined (65). The association of specific subsets ofB-cells with certain lymphomas suggests that some populationsof B-cells are at greater risk for lymphoma development. Examples are the B-cell chronic lymphocytic leukemias and diffuse small cleaved cell lymphoma (IDL/CC lymphoma) thatexpress CDS surface antigen in a high percentage of cases(66, 67). A number of studies have shown that the Igs produced

by B-cell chronic lymphocytic leukemia are autoreactive (seediscussion in (Refs. 68 and 69). In contrast follicular lymphomas do not express CDS, but many of the Igs produced by thesetumors are also autoreactive (70). The CD5+ cells in the mouseare thought to be self-renewing, but is it clear yet whether thehuman CD5+ B-cell population is self renewing? Interactionwith self-antigens may provide the stimulus for maintenanceand self-renewal of these cells and increase the risk for developing oncogenic mutations.

Genetic Susceptibility. In humans there are striking variations in the incidence of different forms of NHL in Asia(71,72), where there is a greater proportion of T-cell NHLs anda difference in the distribution of B-NHLs from those seen in

the United States. Follicular or nodular lymphomas form aminor group in Asian countries (71, 72), while they comprise alarge group in the United States. These findings raise the possibility that the genetic background influences the developmentof specific types of lymphomas. This is an area in need ofinvestigation. There is evidence of genetic susceptibility to B-cell tumor formation in inbred strains of mice. Findings intransgenic mice bearing Eu-myc or Eu-v-abl (40) suggest thatthe genotype of the mouse can influence the rate of B-cell tumorformation or progression. In paraffin oil-induced plasmacytom-agenesis in mice there are strong strain differences as well asevidence that specific genes determine susceptibility and resistance (73).

Summary

Chromosomal rearrangements are a major mutagenic mechanism in B-cell tumor formation. Other biological factors inhuman lymphomagenesis are aging, immunodeficiency, antigenic stimulation, and genetic predisposition. Future workshould be directed toward understanding the factors that increase the rate of formation of illegitimate exchanges betweengenes and the underlying mechanisms of the biological factors.

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1992;52:5522s-5528s. Cancer Res Michael Potter in HumansPathogenetic Mechanisms in B-Cell Non-Hodgkin's Lymphomas

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