Document pBdbbq0q9OeLXVVqk65N2917w

I MECHANISM 0 BLYMPHOMA PATHOGENESIS CV7'JA .\.~LJ ClJ7913 c:onlpnnents of lh ~ ll-ce] receptor that .rrli:::~._Latc signalL.nf!, tOIIo~<vi11g crosslinking. lmtitHtefor Cell Biology (Tumm, Reseanh), University ojDwsburgEssen, iviedical SchooL VirchowstrafJe 173, 45122 Essen, Germany. e-mail: mlf: kuppcrs@ uni-e..sse1u:ie doi 10.1 Q'J~/mcl589 RalfKuppers Abstract IChromosomal translocalior's involving the immunoglobulin loci are a hallmark of many types of B-celllymphoma. Other factors, howeve1, also have important roles in the pathogenesis d B-cell malignancies. Most B-cell lymphomas depend o:l trle expression of a B-cell (BCR) for survival, and in several B-cell malignancies antgen activation of lymphoma cells through BCR signalling seems to be an important factor for lymp'loma pathogenesis. Recent insights into the lymphomagenic role of factors supplied by the microenvironment also offer new therapeutic strategies. In the Wcstnn world, about 20 new cases of lymphoma are diagnosed per l 00,000 people per year'. About 95% of the lyrnphmnas aTe ofB-<-ell origin, ftc rest are T-cell malignancies. This might be surprising at firs! given the similar frequency of B and T cells in Lhe hurnan body, but is understandable considering the specific factors that inl1uence the pathogenesis of B-cell lymphomas, About 15 types of B-celllympboma are distinguished in the current World Health Organization lymphoma classification 2 i-:"AilLE 1 ). The distinction of these lymphomas is not only relevant in terms oflymphoma pathogenesis, but also regarding the consequences for treatment of the patients. This is because the various types ofB-celllymphoma can have very different clinical behaviours, and therefore require diverse treatlnent stlategies. Exciting progress has been made in the past 20 years to elucidate the cellular origin of human B-cell lyrnphomas and the identification ofkey transforming events, in particular the role of chromosomal translocations in lymphoma pathogenesis. However, it is becon1ing dear that B-cell tmnoun are not as autonornous as p1 ..-viously thought- key factors that are cruci:Jl for norm,Jl B-uell diJ.Terenlialion :Jnd survival are also required for the malignant growth of most B-celllymphomas. \'\'hat is the cellular origin of B-cclllymphomas and 'What are the main transforming events? How do antigen activation of the B-cell receptor tBCR) and the cellular microenvironment contribute to the pathogenesis ofB-cdllympbomas7 Cellular origin of B-celllymphomas B-ed] takes place in distinct differentiation steps th<J.t are eharaderizeJ hy the speei fie struLluTe of Ihe BCR. Tht:> BCR is cmnpmcd ol !wo irlcn!ical heavy- chain and two identicallighL-chain immunoglobulin (Ig) polypeptides that are covalently linked disul- phide bridges. Other components o[ the BCR are the CD79"'AND CD79Hinolecules, which contain cytoplasmic immunoreceptor tyrosine.-based activation rnotifs. These motifs transmit signals following BCR crosslink- ing. The intracellular signalling components activated by BCR crossli nking include several tyrosine kinases. Depending on the djfrerentiation stage of the B cell that recognizes an antigen and on the activation of other H-oell surface receptors that modulate BCR >ignalling, the activated B cell might he induced to pro]iterate and/or undergo further diflerenliation steps". Early B-cell development, which occurs in the bone nrarrow, concludes when a B-cell precursor suc- cessfully rearranges lg heavy- and light-chain genes and is equipped with a functional surface antigen receptor (FlG.l). Cells that express a functional (and uon-autme<Jctive) BCR differentiate into rnature naive R cells and leave the bone marrow, whereas B-e ell precursors that faiJ to express a ECR undergo apoptosis3 Mature naive B cells can be activated by antigen to the BCR and participate in immune responses. In T-celi-dependent immune responses, antigen-activated l::l cells undergo clonal expansion in structures called 'germinal centres' NAH;RF REVTEWS I CANCER 2005 Nature Publishing Group I IVOU!l\IE _i APRIL 10115 251 CGU BEN0000243 R SUmmary A haliniark of many types ofB-ccll lymphoma is redproc:iJ chromosom.d translocations involving one ofthe immunoglobulin loci and a proto-oncogene. As a cnnsequence af such translocation&, the oncogene comes under the control nfan active immunoglobulin Incus, causing deregulated, constitutive expression ofthe translocated gene. Nunmil B cell, depend un B-cdl receptor (BCR) eJLJn-ession fur survival T11e odection for i!xpressiun uf a BCR ahu see-ms tu cells. Although there is strong evidence that most B-celllymphomas depend on RCR expression, there are a tE.v exceptions- namely classical Hodgkin's lymphoma, primary mediastinal B-cclllymphoma, some post,-transpl<mt lymphomas, and the rare primary ef!usion lymphomas. In several lymphomas, there is a strong indication that the lymphoma celllsre<:OJ~llze an antigen and that stirtmlationby antigen binding contributes to the su.rvhml and proliferation oflymphoma cells. In many lymphomas, such as tollkular lymphoma,m'-tcosa-asoodated lymphoid tissue lymphomas and classical Hodgkin's lymphom4, the t~tmour mkroenvinmment seems to be important for the survival and/or proliferation of the lymphoma eclls. The recognition that the survival and/or proliferation ofmany B-celllympho:rnas depends on their interaction vv:ith other cells in the microenvironment, as well as on expression of the B-een receptor and, sometimes,antigen activation,:might lead to novel treatment options forB-cclllymphomas. (GCs), where the the Ig genes are modified by somatic hypermutation and dass-swikh recombination (FIGS 12 ;, As distin..:t stages ofB-cell development and differ- entiation are characterized by the particular structure of the BCR and expression patterns of differentiation markers, and as these processes often take m spe- cific histological structures, analysis of these features wa.-; used to determine the origin of the various hurnan B-cclllyrnphomas4o (Tf\BLE 1I. T'lw rationale Cor such a chssification of B-cell lymphomas is based on the observation that rnalignant B cell:; seen1 to be 'frozen' at a particular di1Ierentiation stage, which reflects their ori- gin '67 One of the main concepts emerging t1,om these studies is that most types of B-celllymphoma are derived from GC or post-GC B cells'-' {llOX 1). The cellular origin of B-celllymphomas was further clarified, and previously unrecognized distinct lym- phoma subRJJes ,-~;-ere also identified, by gene-e:qJression profiling of human B-ee!! lymphomas and normal B-o;-1! subsets_ Such studies identified, for example, a GC B-cell genc-e:x.-pression signature that is associated with follicu- lar lym.phoma, Burkitt's lymphoma and a subset ofdif- fuse large B-celllymphomas'. These findings supported the C~C B-cell origin of these tumours. (~ene-expression profiling studies of other malignancies also revealed unexpected relationships, in tenns ofgene-expression patterns_ For exarnple, in addition to B-cell chronic lyrn- phocytic leukaemia (B-CLL) cells with mutated ]g vari- able (V)-region genes, B-CLL cells with unrnulated Ig V-region genes showed greatest similarity to memory B cells that had undergone somatic hypermutation, indi- cating that both subtypes of B-CI.l. are c-elated to men- ory B cells". 1\Ioreover, a subset of diffl1se large B-cell lymphomas was identified that, among the various H-cell subsets included in the analysis, most closely resembled in-vitro-activated B cells' In these cancer cells, the trans- fonnation process n'ight have been associated with an alteration uf the g<:ne-expiessiun pwflie, masking the sig- nature of the cell of origin, as seem,; to be lhe case in clas- sical (see below). It is also pos,;ible thar the normal B-cell counterpart of some cancer types might not have been identified yet. In the activated B-cell 'tJ1'e of diffuse large B-celllyrnphoma, the normal coun- terpart could be a poorly defined, small subset of GC H cells that is undergoing plasmacytoid differentiation, or a post-GC immunoblasl population7 Transforming events Reciprocal chnmH>,;onl<cl translocations involving one of the Ig loci and a proto-oncogene are a hallmark of many types ofB-celllymphomaW1' !1AJ3LE21. As a con- sequence of such translocations, the oncogene comes under the control of the active Iglocus, causing a dereg- ulated, constitutive expression of the oncogene. Three types of breakpoints can be distinguished in the Ig loci, Some translocation.~, such as the BCL2-fgHtransloca- tion associated \'>'ith follicular lymphoma, have break- point:> that are directly adjacent to Ig heavy chain J-regio11 gene segments or that are to regions where the Ig heavy chain D-region (D, 1) joins the )-region ([\)nl {l'lC.IJ, As the brea.kpoints also often show loss of nudeotides at the end of the JH or Dn seg- ments and the addition of non-germline-encoded nudeotides- typical features ofV(D)f recombination - i t is likely that these translocations happen as mis- takes during V(DH recombination in early B-cell devel- opment in the bone marrm'i'-H. In other translocations, the breakpoints arc found within or adjacent to rearranged V(I1)J genes, and these \ 1-reglon gene.'t ar~ somatically mut<~lccL These and :1ddilional Cca- lures indicate that such translocations occur as by-prod- ucts of the smnatic hypermutation process1"15, which is associated v,ith DKA strand breaks10- 17 The third type of translocation is characterized by breakpoints in the IgH const;mt region switch regions, in which DNA breaks are introduced during class switching. This indicates that these events occur during class-switch recombination. The causes for the generation of DNA strand breaks in the oncogenes involved in Ig-associated transloca- tions are less clear'u Some of these genes, however, undergo aberrant smnatic hypermutation, and there- fore acquire DNA strand breaks in the same regions where the chromosomal breakpoints are located (see helow) 18 Regarding the BCL2-lgHtranslocations asso- ciated with follicular lymphoma, it was recently shown that the DNA in the major breakpoint region of the BGU gene often acquires an altered structure that is cut by the RAG nudeases, which mediate V(D)T recombination. This finding indicates that in these translucations, Ri,G- medialed DNA cleavage is responsible for Lhe D"JA breaks in both partners involved in the transloc<ltion19, RAG enzymes might also be involved in chromosomal trmHlocations through another mechanism- RAGs have heen shown to possess transposase activity, so some translocation events could be explained by double-ended transposition events'u.21. I I252 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000244 R ws Table 1 I Human mature B-celllymphomas Lymphoma Features B-cell chronic lymphocytic leukaemia (B-CLL) Leukaemia of small B cells that express the CC5 artgen, involving peripheral-blood and bone-marrow cells. Cornman in elderly patients. 0alled 'small lymphocytic lyrnphor1a' when lymph-node cells are predominantly involved. Patients wth leukaemia cells that l<tck variable (\1)-reoinn gene mutations have a worse rrnonnsis thnn patients with mutations in V-region genes. Mantle-celllyrnpl101 rJH orises frum cells Iflat populate 1ile mantle LUlie ui express CD5 ard show abemation in cyclin-01 expression. Nearly all cases are associated with BCL 1-lgfi tt-anslocation. B-cell pmlymphocytic leukaemia Cnronic 8-cellnaligr.ancy related to B-CLL. Over 50% ot cancer cells represent prolymphocytes (large lymphocytes with clumped chromatin and prominert nucleolus). Follicular lymphoma A nodal lymphoma with a follicular growth Lyrnphoma cells morphologically and phenotypically GC B cells. Most cases are associated with BCL2-/gH translocation. Hairy-cell leukaemia C'lronic B-cell naligrancy involving spleen anc bone marrow. few circulating leukaemia coils. Tumour coils form 'h;::;ir/ Frequency among lymphomas (%)* 7 Proposed cellular origin Memory B cell? Nave B cell'I Marginal-zone B cell? 5 CDS marde-zolie B cdl <1 MemCJryBcell 20 GC B cell <1 Mem8ryBcell MAU tyrnphoma Extranodal marginal-zone B~cell ~;nphoma, Develops most~; In aquired lympho:d struc.;tures. 7 Marginai-Z8ne B cell Nodal margilal zona lyn1phoma Lvn:phoma with primary presentation in lymph nodes. Lymphoma cells resemble marginal-zone or monocytoid B cells, but olter1 have heterogenous cytology, which ranges from small to large lymphocytes ar1d ncludes plasma cells. 2 MarginoJ zone B coli? Monocytoid B cell? Splenic marg'nal-zone lymphoma Micron ocular lymphoid infiltracion ir, the splenic white pulp. Mostly smalllgD lymphoma cells that normal follicles and the marginal-zone region. Frequently infiltration nto bone marrow and circulation. Subset of naive B cells that have differentiated inlo B cells'? Burkitt's lymphoma Fast growing. lvlostly extranodal. Characterized by a translocation. Patients with endemic form are El:3\/-oositive nearly all cases. Patients with sporadic form are FR\i-posicive in about 30% of cases. 2 GC 6 cell Diffuse large B-cell lymphoma Heterogenous group oftymphornas characterized by large B cells. Several subtypes are recognized. Morphological variants include centrobla.sts and imrnunobla.sts. 3(}-40 GC or post-GG B cell Primary mediastinal Bcelllylllphoma Subtype of diffuse large 8-cel! lymphoma located ir: the rrediastinum. Tumour cells are larqe B cells but also sho'N a number of similarities tc: Reed-Siemherg ~:ells of classical Hodgkin's lymphorTH Most frequently occu1s in your,g won en. 2 Thyn:ic B cell Post-transplant lymphoma Mostly ofthe diffuse large-celllycnphorna type. Lymphomas that arise in patients alter organ transplantation. Immunosuppressive lre;atrne;rtconfers ri;:;k of ~,;n.:;ontrolle;d proliferation of EBV-infected 8 cells that can develop into lymphomas. GCRcdl Primary effusion lymphoma Frequently occurs in patents vvith AIDS or patients who have <0.5 mceived organ transplants. Lymphoma cells are found as effusions in serous cavities, such as pleura, pericardium O' peritoneum. (P:Jst) GC B cell Lyrnphoplasnlacyt'c lyrnphoma Involves lymph nodes, bmo marrow and The tumour-cell population is composed small B cells, plasmacytoid lymphocytes and plasma cells. Most patients present wth a serum monoclonal protein usually of the lg~,A type. (P:Jstl GC B cell Multiple myeloma ~~eoplastic proli;eration of plasrra cells in the bone marrow. 10 Plasma cell Classical Hodgkin's lyrnphoma U1aracterized by bizarre, large tumour cells. Hodgkin and Reed-Sternbe!'g cells account f.::w less than 1% of cells in the tumour, and are admixed with various non-neoplastic cell tYJJes. Tumour cells show a phenotype not characteristic of anyncrrnal haematopoietic cell type. 10 Defective GC B cell Lymphocyte-predominant Hodgk:n's lymphoma Rare indolent subtype of Hodgkin's lymphoma. Lymphoma cells show a 8-csll phenotype, represent a small population in the tissue, and grew ir1 association with follicular denjritc cells and T-helper cells. Good prognosis. J.5 GC E cell +Thsse numbers refer to ::he fm-qusnci,::;s :n Eumc-e and North .1\rr:erica. A!DS. acqu:red imrnur:e deiici3r'1Cy' syndr:J'lle; EB\1, Et=Gt3in -BErT -\/.rus; !g, immun:Jglobul:n: ~,J!f\LT mucosa-gssoc,ated ly~l'phoid "t::ssLe: GG. germinal centre. ~An;Rt: ]{EVrEws 1 cANCER 2005 Nature Publishing Group I IVOl.llf\lE 5 APRIL 2005 253 CGU BEN0000245 R a VDJ recombination b Somatic hypermutation c Class switch I:=;~Jure; 1 Molecular processes that remodel immunoglobulin genes. In 1rr 1ur 'ugldJulins {lgs) are c;xpressed Ly B cells ar d consist of variable(\/) reqions, vvhich interact with antiqen, and constant (C) regions. which mediate the effector fue1ctions d iqs. To create a functi::>nallg, B cells must rearrange DNA segcnents ~hat encode the h'lavy (H)- a'!d light-chain (not shown) regions of the Jariable genes. a First. tnrough "'process cal:ed 'VID)J recombination', three 0ene segments, nrl and ,Jrl, are joined to encodB the +chain variable region. 'he V regiors of lhe K- and ),-light chains, alternatively, are each by lwo gene segments- \he V, and J, genes (r1ot shown). R-cell precursors iirst carry JUt LJH-J 1 rearrangernen;s tn H-cliain genes. These D, 1-J1, rearrangements are iollowmi h y \/ , 1 - 0 "1 1 1, rnammgrnlf>l~lls, ms1Jiling in lhc expression of Fl prre-B-r:dl rcxxplnr i' lh~; marrmlgc:rn>J~Il prmh:clivC>3 ArJoc,l EiO functional VH gene se;)ments, 27 DH segmcmts ard 6 JH segmencs are available in the germ line, allcwhg the generation of a diverse cepert::Jire oi V" gene rearrangements. ~, he diversi~y is turtller i:1creased by the 2ddi:ion or removal oi r:ucleotides at tre joining sites ci the gene se-;Jrnems3 . The cells then carr; oul rearrangements al their L-chain loci (nol sh-ovm). The \!-region of the lg gene is ui,Jmalely I::ornocbd to the :::;-reg.on of the lg gene (G,ll of lgM in diagram) b The process of somatic hypclnrutation is activatej when B cells reach the gom:nal centre (C:C, shown in more dmails in FIG~ 2). Illis prnsoss leads to tile introdLrction of poi:~t IT'Utations, (Jllietiors or dupli::atbns in the rearranged '!-region of lg genes (denoted by 'Xs' in the iigure/02. Trese mutations occur in the \/-region of lg genes I-not in the downstream G~L reg:on. c Class svAchir,g results :n the replacement ofthe originally expressed H-crain G-re;JiOCl gene wilh that oi amther lg gene. In the diagram, the C-regbn lor lgM (Gil) and IgO (Cii) ara exchange,j Jorthe C-region ollgG (Oy11 by ecornrJic1ation at the switch regions tor these gerJBs (Sp ancl Syl, respectively). ihis results i1 an ar,tibocly with different effector functions but the same antigen-binding doman. CD95 Cell-surface -receptor thac n1etliat{:-S apoptosis signalling_ The pmce,;s of somatic hypermutation conuibute;; to lymphoma pathogenesis not only by causing chm- mosomal translocations, but probably also by targeting non-Ig genes. Two situations have to be distinguished. 11u: genes encoding and CTJ'h (also knmvn as !'AS) were found to contain mutations in a considerable frac- tion of normal Gf: and Tnnnory B cells, indicating that !hcse gcn!'s arc ol!en large ted by ihc hypcnnulaLion machinery in normal B cells''-24. Tn rare instances, such m.ulations might promote the developrnent oflyJn- phomas. For example, inactivating mutations of are found in about 20% of (post) GC B-celllymphomas and could pwtect lymphoma cells from death induction by CD95-ligand.-cxprcssing cells", In the case of the BCL6 gene, the frequent occurrence ofhypermutation might also cause translocations of this gene into Ig- as well a~ noo.-Ig-encoding loci. This possibility was indi- cated by the finding that the 5' region of BCL6, which is the site ofhypcrmutation, is also the region where chromosomal-translocation breakpoints are mostly found1"2'. In diffuse large B-celllymphomas, aberrant hypermutation of multiple oncogenes has been reported, which might also represent an imporlant mechanism ofpathogenesis". Two of the molecular processes that could cause chro- nwsorne translocations or n1utations in non-Ig genes ou.m exclusively (or at least mainly) in the GC - soma lie hyperrnulalion and cbss-svvilch recornbinalion26 . This could be one of the reasons that most B-celllym- phomii.s derive from GC B cells or their descendents. Class switching and somatic hypermutation do not occur in the DN/\, ofT cells, which could also partly explain why H cel1s are more prone to undergo malignant transfonnation than T ceLL>. Vv'hereas chromosome translocations involving Ig loci are dearly a hallmark ofmany types ofB-celllymphoma, many other transforming events have also been implicated in the pathogenesis of lymphomas, such as 1nutations in tumour-suppressor genes (such as and the gene encoding genomic arnplifications (such as and lTan.,]oLations not involving Tg loci ('L\BLE Finally, viruses might also be involved in the trans- fornration ofB cells. The most well-known rs Epstein-Barr virus (EBV), which is 1ound in nearly all endernic Burkitt's lym.phmnas, in Tnany post-transplant and primary effusion lymphomas, and in about 40% of cases of classical Hodgkin's lymphoma (sec REFS 27-.lO for reviews) (TABLE 2). Another member of the herpes-virus family, human herpes virus 8, is implicated in the pathogenesis of primary eff1rsiorr lymp:1mnas31 The oncogenic features of herpes virus 8 are not well understood, but it was recently shown that the viral pmtein FUP activates the transcription factor NF-KB, which is an important survival fa.::tor in primary effusion lymphoma cells30 Role of the BCR in B-eelllymphomas Role of the BCR in the survival of normal B cells. Throughout theiT lives, B cells undergo stringent selection fm expression of the appwpriate BCR. Pre-B cells are selecled fur a pre-RCR (composed uflg heavy chains and surrogate light chains), and immature B cells are selected tor expression of a non-autorcactive, functional BCR After these steps, GC B cells are only able to survive the GC reaction and differentiate into memory or plasma ceLls if somatic mutations in their V-region genes result in e.Al'ression ofa BCR with increased affinity for a I I254 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000246 R ws Plasm8 cell Memory B cdl 21Figure B-cell differentiation in the germinal-centre reaction. r,ktc~re {naive) ,:;ntgen-activated B cells that recei\/e signas krowrJ as Fcell help' are driven into primo.ry B-cell rollicles in secondary lympnoid orgars suc'l as lymph nodes, where tlley establish germnal centres (GCs; lightest yellcw region) 103. The naive lgiWigD' 3 cells that constitute the prirlar; B-cell icllicle are replaced by the proliferating GC B cellc; und cis[Jiacod to tile oJtsido ot tr:e follicle, whore they torn 1 u nE;ntle zone iJ.rDLP.ld the GC. In the G0, a da'k zone arcJ a light zone can be disTinguished (left 8.nd right sides. respectivery). The dark zone mainly consists of pr::>liierating GC B cells. whereas the GC B cells in the iight zone are resting m. In pmiiferating GC B -~eils, the pmcess oi somatic hypermutation is activated, which leads lo the intmdLcction of mc1\ations at a high rate into the (ea,ranged lg variable (V1-mgion geres of the B cells"''. Most mutations are disadvantagous for the cells- such as those that ;ead to reducec affinity of the BGR for antigen ar'd ~ause eelis to undergo apoptosis. /\few GC B cells will acquire mutations in the BCR that increase their affinity 1or antigen, and those cells will bo positively selected. Tho soloction pro~0ss prosl;mably takc.,s mainly pi aGO il" tho light zom, whore tho GC B 0olls aro in close contact with CD4+ T celis and follicular dendritic cells (FDCsi. A fracticn of these GC 8 cells undergo class-switch recombinalion ' " 4 fin :illy, GC B cells differen\ia:e ,nto memDry B cells or plasma cells and leave the GC microenwo'lrrent. ANTT-TDTGTYPTC ANTTROllTPS Antibodies that bind to tile unique derermlnants in the V-r~gion o( <'lrtnth::r antibody_ cognate antigen'. Even mature resting B cells arc con- stantly under sdeLtive pressure lo express th.: RC:R- ablat ion of BCR expression in mice leads lo the apnplolic death of B cells:<'-3". So, it seems that this BCR dependency is a main determinant ofB-cell sur- vival. IL is still debated whether the survival signal sup- plied by tb.e BCR is an autonomous signal or is initiated bylow-level BCR activation by antigen. BCR dependency ofB-celllymphomas. The selection for expression of a BCR also seems to occur in malignant B cells. Indeed, most B-celllymphomas stiil express a BCR, although smnetimes at relatively low levels-'"-" (HOX !). The proposal that there is a need for BCR-dcrived sur- vival signals is the observation that translocations into the Ig-loci are virtually always found on the non-productively rearranged Ig loci, vrith a few exceptions". As the three Ig-gene-ren10delling processes that are implicated in the generation of these translocations- V-region gene recom.bination, class switching and somatic hypermutation <FIG. , . - prinLi- pally o<.:cm in both Ig alldes, translocation events should happen al nearly equal frequency on the expressed Tg allele and the non-expressed allele. However, as the expressed Ig alleles are not found to be inactivated by translocation events, it seems tr.at at least at the time that the tr:mslocations happened, the inability to form a llCR was incompatible with survival of the cells and development into a B-cell tumour. Further evidence that the BCR supplies in1.pmtant survival signals tn B-Ldllymphoma cells is provided hy the ohserv:Jlion thallrealmenl of patients who have fol- licular lymphoma with ANn-mroTYPrc .;NTmonn'S did not result in the ernergence of BCR-negative lymphorna varianls - either through downregulation of BCR expression or by selected outgrmvth of clones with inac- tivating Ig V-region gene m.utations"" w Finally, several types oflymphoma show ongoir:tg V-region gene muta- tion during tumour clone expansion"04 '-lo. As a consid- erable fraction of mutations would interfere with BCR expre~sion or function, such as nonsense mutations or replacement mutations that prevent proper heavy- and light-chain pairing, it is notable that such lymphomas also retain RCR . Indeed, it has been deter- mined that two types ofdestructive somatic mutation -nonsense mutations and deletions or duplications causing reading-frame shift:;---- account for nearly 10% of mutation events, it mutations accumulate under non-selective conditions 15"'- So, the rare occurence of BCR-loss variants of lyrnphomas with ongoing sonuti<. hypermutation, such as follicular lymphoma, Rurkill's lymphoma, lymphocyle-predominanl Hodgkin's lymphoma or mucosa-associated lym- phoid tissue (MALT! lymphomas, is a strong indica- tion that lymphoma cells undergo ,;election for BCR expression. Therefore, the survival signals supplied by HCR expression in normal H cells might also promote survival of B-celllymphoma cells. ~An;Rt: ]{EVrEws 1 cANCER 2005 Nature Publishing Group VOUif\lE 5 I APRIL 2005 I 255 CGU BEN0000247 R Exceptional B-celllymphomas I hat do not express the BCR. Although evidence is strong that ITlost B-cell lyrnphurnas depend on BCR expression, there <He a few exceptions (BOX 2 . In classical Hodgkin's lymphoma, inactivating TgV-region gene mutations that render originally functional V-region gene rearrangements non-functional were detected in 25% of cases"". }\s ollly a small fraction of inadivatiug mutatious that occur in mula ling GC B cells can easily be identified (for example, nonsense mutations and deletions), it is Box 1 I Cellular origin o1 human B-cell lymphomas Human B-cell lymphomas are assigned to their proposed normal B-cell cmmterpart. Most lymphomas are derived from germinal-centre (GC) R cells or from R cells that have passed through the GC, indicating its role in the pathogenesis of R-cclllymphnma. As shown in the figure, the GC is surrounded bya mantle :mneof naiv,e R c.ells, most ofwhich <"<:press the cus marker- tht:se might wmprise a distim:l B-cdl ~ubseL Tiu: umrginal zum: is a B-c:dl-rkh zone located between Bu:ll fullides and the Tcell area. in the spleen (a similar n;gion is pn:;,ent in Peyn's paldteb, but usually nut in lymph nodes). The origin ofmarginal-zone R cells is debated. and probably includes postGC memory B cells and naive B cells involved in T-cell-independent immune responses. Extranodal macosaassociated lymphoid tissue (MAJT) lymphomas and nodal marginal-zone B-celll:yn>phmua.s (not shown) are presunmbly derived from nmrginal-zone B cells. Splenic mannntm-nmeB-celllymphomas comprise both follicular an:d cells, and often cany unmutated variable (V)-region genes. These lymphomas might therefore be derived from naive B cells prone to undergo marginal- zone B-cell differentiation tDs. Whereas most mantle-cell lymphomas are believed to be derived from CDS~ (naive) B cells of the mantle zone, about2fi-30% of cases carry mutatedV-rcgion genes, indicating that theyhave passed through the GC. The origin ofB-cdl chronic lymphocytic leukaemia (B-CLL) ccll.s has been debated. About half of the cases of B- ClL carry mutations inV- region genes. Both subsets ofB..CLL have been proposed to derive either from CDS+ B cells, memory B cells or marginal-wne B cells10'. Post-transplant lymphomas, which often develop in patients after organ transplantation, are often derived from antigen-selected, BCR-expressing {:;c B cells, whereas others might be derived from pre-apoptotic GC B cells''-". Gene-ex-pression profiling identified two main subtypes of diffuse large B-c>ell lymphoma (DLBCL), one>\ith a profile resembling GC B cells {GC-type), and the other resembling in- vitm-activated B cell.s (ABC-type) 8 . Primary mediastinal B-celllyrnphomas are believed to be derived from post-GC B cells of the thymus_ Solid arrows denote B-ed! differentiation steps and broken arrows assign the various lymphomas to their proposed normal <:ounterpart. I MALT lymphomaj I Multple myeloma . ens A cell-surfa~e glycopmteln that is e""q.lressed by virtually all T cdls and J. _-;ubset of B cells. I I256 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000248 R ws possible that Hodgkin and Heed-Sternberg (HRS) cells - the tumour cells in patients with classical Hodgkin's lymphoma- iu most if uot all cases are derived from pre-apoplolic GC B cells Lhal have losl the capacity to express high-affinity BCR. How can HRS cells escape selection to evade apoptosis? ln about 40/c, of cases of cla,;sical Hodgkin's lymphoma, I-IRS cells are infected by F.BV and express the EBVencoded latent membrane protein 2A (LMP2A)". LMP2A harbours an immunoreceplor tyrosine-based activation motif, which is also found in the ( and (also kn<Twn as Igu and Ig~, respectively) molecules of the BCR and is required for BCR-rnediated survival signalling33 .Studies of transgenic mice that express LMP2A in B cells have shown that LMP2A expression can replace the BCR-mediated signals'18,'"'. So, expression of LMP2A in an ERV-in tected GC B cell that is undergoing hypermutation might rescue the cell from apoptosis following acquisition of untavourable somatic V-region gene mutations. i\fter acquisition of additional transforming events (other than EBV infection), that cell could, in rare instances. give rise to an IIRS turnotu done''". The role of LMP2A iu the establhhed HRS cdl dune, howewr, is less dear, because HRS cells have downregulated expression of central components of the BCR signalling cascade'". including spleen tyrosine kinase (SYK) and SLP65, which seem to be essential for the function ofLMP2A as a BCR surrogate' '2 Indeed, HRS cells have lost c)cprcssion of nearly all B-cell-typical genes""jJ''4 \Vhether this 'lost B-cell phenotype' is directly related to pathogenesis and/or the presumed derivation frcnn crippled GC B cells is unclear. Perhaps, for a GC B cell, which because of disadvantageou' son1atic mutation,, doe~ not receive appropriate survival signals and would therefore 'l.ormally undergo apoptosis, it is advantageous w lose its B-cell identity as a means of becoming independent from the stringent selection for expression ofa (highaffinity) BCR Such a phenotypic change migbt be promoted by, or depend on, transforming events involved in HRS-.::ell generation. Alternatively, the loss Table :;> I Mechanisms of B-cell lymphoma pathogenesis Lymphoma rvirtntiA-cAIIIymrhnmA Chromosomal translocations CCND1-fgH (%) 17 " Tumour-suppressor gene mutations ATI'vl (40)'"''"" B-cell chronic lyrnphocytic leukc1.emia Follicular lvmphoma Diffuse large Bcell lymphoma Primary mediastinal B-cell lymphoma BCL2-/g/-! (80)"-" BCL6'-various BCL2-1gH 1\WC-/al i 0' MYG-fgL (15)-" coos ATM TPE-.3 SOCS1 (40)'" Burkitt's lymohoma MYC !gL .RB2 P::Jst-transplant lymphomas Classical Hodgkin's lymphoma Lymphccyte-predominant Hodgkn's lymphoma Splenic rnarg'nal-zone I',C'Tiphoma rv1ALT lymproma Lymploplasnacytoid lycr~phoma Primilry p,ffllsion lymphomil Multiple myeloma BCL6-various {48)''3 APi2-MALTI BCL1D-igH MALT1-!gh FOXP1-Igh PI'X5-IgH (50/42 CCND 1 ioH (15 2011 " FGi=F<3-igH (I 0)14', ' ' MAF-IgH (5-1 0)' "'' !KBA (1 ,_.,,,n,.,-.~ (10)'"'. C095(10)1 '17 Viruses EBV i90)'' EBV/40)2' Other alterations DCJIAtion Oil i ;ic 14 (50-70) 110' Deletion on 13q 14 (6C)n4* Aberrant rypermutaton ot proto-cncogene& Aber~ant hypermutaton of mul~iole proto-oncogenes (70)!03 .REL amplifications (50) 132 Deletion on 7q22-36 (40)1o4' Indirect role of in Various MYC alior<Jtions (40)"18, RAS mutations (40)'c", deletion on i 3qi 4 {50)"5"' ::tpoctosis titnblaEt growth 'actor mucosa-associ2.terl tissue; /VIALTl, mucosa rntinnlhlac;tCJmPt-rc:lril< "' gene 2SOCS1, supprcGGor of o;tokino aigrwl!ing :, ~An;Rt: ]{EVrEws 1 cANCER 2005 Nature Publishing Group VOUif\lE 5 I APRIL 2005 I 257 CGU BEN0000249 R Box 2 I The B-c::ell-rec::eptor dependenc::y ol' human B-c::elllymphomas Different types ofB-celllymphoma express different levels of H-cell receptor {BCR), or BCRs with diffeorent specificities or levels or activity. Listed below are the details of BCR function in these various cancer types. Lymphomas that express HCR Mantle-cell lymphoma. Diffuse large B-celllymphoma. Splenic marginal-zone lymphoma. Lymphocyte-predominant Hodgldn's lymphoma. Hairy-cell leukaemia. Prulymphuqti<: leukaemia. Burkitt'slymphoma. Lymphoplasmacytic lymphoma. Lymphomas associated with BCR expression and indication for antigen a;;;tivation Follicular lymphomas aTise and grow in the germinal centre "nd in some patient samples the BCR is autoreactive. The BCRvariable donmin containsmutations that promote carbohydrate modification. Gastric mucosa-associated lymphoid tissue ly:mphmnas are in1nany cases associated with auton:adive BCR, particularly with rheumatoid factors. B-cell chronic lymphocytic leukaemia has a restricted variable IV)-region gene repertoire and the BCRis often autorea~i:ive.ABCRspedficto human T-cdl lymphotropk virus I has been identified in patients who arc infe<::ted with this virus. In hepariris C virus (HCV)-associareii lymphoma,,, HCV-specificity ofBCRhas been reported in some cases. Disease regression occurs after antiviral therapy. In primary central nervous system lymphomas, about halfthe cases express the same heavy-chain (VH) gene segment CVH4-34), whereas other genes of the BCR are diverse, .indicating tumour-cell stimulation by supcrantigm binding to the BCR. Lymphomas that do not express BCR Classical Hodgkin's lymphomas are associated wilh inactivating immunoglobulin {Ig] V-region gene mutations in at least 25% of cases. Transcription factors that promote BCR expression are d<rNnregulated. A transcriptionally inactive chromatin structure is seen in these lymphomas. In post-transpl~nt lyrnplwmas, inactivatingV-region genPTnntations are obse1-verl in at least 1{}-20% of case;;. Primary effusion lymphomas are not associated with inactivating lgV-region gene mutations. However, dmrnreguiation of transcription factors that promote BCR cxprcssi(m is seen. Prinlarymediastinal B-celllymphomas are not asso.:iatoo "ith inactivating Ig .V-region gene n~utations. Expression oftranscription fadorsthat regulate RCR expression is seen, but internal Ig enhancer activity is downregulated. CD!9 B-ccll-,spccl1ic ,o;urfacc molecule e>cpn::ssed !rum Lhe earli~~l B--e-ell rrec.ursor sbges np to the plasmablast stage. Regulates. the responsiveness ol-B cells f.,_J11ovving 3-ce1l-''"CCCptor cro5slinking,. cn:w H-('ell-spedfic s.nrfnc2 mark:.:r expressed by pre-B ~md all rnature R c-tHs. Dovn:regulated on plasma -cells. of the B-ed! phenotype might be largely unrelated to derivatioc fTOm crippled GC B cells, and might instwd reflect transforming events in HRS-cell pathogenesis that render the cells independent trom expression of a BCRO As a consequence, the HRS cells would no longer be under selective pressure to rnaintain their B-cdlspedfic expression progra1nme and could adopt anolher phenolype. Lymphoma clones with inactivatingV-region gene mutations have also been observed in a fraction of cases of post-transplant lymphomas''-"0 These are usually EBV positive and express all latent EBV genes, so it is possible that L\IP2A promotes the survival of these crippled lymphoma cell so The requirement for BCR expression is unclear in. pri- rnary mediastinal B-celllyrnphmnas. These lymphomas la~k detectable BCR ~xpressiun and have duwmegulated expression of componen ls of Lhe BCR signalling cascade and activity of the intem:Jl IgH eDhancer, but no samples with inactivatingV-region gene mutations have been described"c~-',u. Recent gene-expression studies revealed, surprisingly, that primary mediastinal R-celllymphornas arc in many aspects closely related to H RS ccUs of classical Hodgkin's lymphoma, and are more similar lo this lyrn- phoma than to other diffuse large B-ccllly<nphomas. But unlike Hodgkin's lymphomao mediastinal lymphomas have largely retained a B-cell gene-n11ression pattern and are not associated with EBV infection"''6l In the rare primary effusion lymphomas, BCR expres.sion is usually very low or undetectable, but no cases with inactivating mutations have been reported63- 6 '. Notably, these lymphomas also lack e:x1Jression oftbe transcription factors t, and , which arc important regulators of Ig transcrip- tion'"'o The loss of these transcription ta.::tors .::auld the downregulation e:;,.lJrcssion in primary effusion lymphoma cells. These lymphomas also usu- l<Jck detectable exprt"ssion of other B-u~ll m;J rkecs, such as co 19 and CD2D, indicating a loss of the B-cell phe- notype in the effusion lpnphomas that is similar to that of classical Hodgkin's lyrnphomas, although sev- eral aspects oftheir phenotype are also compatible with a plasmablastic differentiation67 Antigen activation of B-cell lymphomas Ts the ability of the BCH to transmit survival or its ability to intexactwith antigen to activate lymphocyte proliferation, required fin~ lyrnphomagenesis< Stuclies in ~evenl difln<"nilymphorna iypcs have indicated !hal lymphoma cells recognize antigen, and that stimulation by antigen binding contributes to survival and proliiera- lion of lymphoma cells (BOX2). This concept was first proposed 1nore than 4U years ago66 In B-CLL cells, the BCRhas been frequently shown to bind At'TOANTrGE'JS''"70 . In sonrc cases, however, B-CLL cells show specificity for foreign antigens, suc:h as viral proteins- this is the case in B-CLL that is pos- itive for human T-lymphotmpic virus type I (REF 7!1. Moreover, seven subgroups ofB-CLl have recently been identified that show strikingly similiar V" and VL gene-rearrangen1cnt ~equences among members of a group;'-~"'. /~!though it is possible that this finding is due to derivation of the lymphoma cells fmm a so-far- unrecognized B<~cell subset with a highly restricted V-region gene repertoire, it is more that this ret1ects selection and activation of these cases by a restricted set of iuVIJGENIC HlTUl'tSo In line with this view, five of the seven groups identified belong to the sub- class of unmulaled R-CLL, which has a phenotype reminiscent of antigen-activated B cells"'. Restricted V-rcgion gene usage is also a hallmark of pri1nary central nervous syste1n lymphoma. However, unlike the situation with B-CLL, this restriction only holds true for the expressed VH gene segment, which is the same in about half of the casesHO''. This indicates I I258 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000250 R ws ,\UTOAKTTGEN A componenl of Lhe body lhat is recognized by antibodies o-f the: indi,~dual's own B Us. "1.NTH~FWIC F1-'1TOl-'FS Sites on an an tig-cn that arc recognized by an mt~body S l l'ERANTlG1:~ Dinds to con~nvcd region(; r th~ the B--cell rc..:.eptor, and thaefore stln1ulates many B cells. C1J4 Co-receptor for n1ajor histoco:-np:atitibi~ity complex d:1s...; II on T-helpcr cdls. CD-10 Receptor tor co-:-timulatory signals for B cells. CD4lJL Tigand fur CLl4U, e-~1-"'~ressed on T cells. binding of an antigen exclusively to the VH gene segn"lent, and that antigen n~ight therefore be a sunJZ- ,\NTIGEN. So, stlnrulation ofB cells a supe1antige11 mighl be involved in lhe palhogenesis of primary central nervous system lymphomas. Studies also indicate a role for antigen activation in the pathogenesis of follicular lymphoma. First, lym- phoma cells from several patient s;unples were found to express BCK with auton~activity''- Second, follicular lymphoma cells show Dngoing somatic hypermutation during tumour-done expansion, and the pattern of these mutations is indicative of their selection by antigen79 Third, about 80% of follicular lymphomas carry smnaticV-reginn gene mutations that result in the generation ofcarbohydrate-linking motifs"'- Such muta- tions were also found at a similar frequency in endemic Burkitt's lymphoma, but are present in less than l 0% of cases ;>.IAIT lymphoma or nonnal B cdls"051 The strong selection for the acquisition of car- bohydrate modifications to the BCR V region offollicu- la;- and endemic Burkitt's lymphoma cells indicates that these moieties are important for lymphoma formation. It is unclear whether the carbohydrates are involved in the recognitinn of antigens or in the interaction of Ihe lymphoma cells with stromal elements. Hepatitis C virus (HCV)-associated B-celllym- phomagenesis has been associated with viral antigens. One study demonstrated the direct binding specificity of the BCR for a viral-envelope protein82 Importantly, treatment of several patients with llCV-associated splenic B-celllymphomas with anti-viral interferon therapy not only eliminated the virus, but also caused regression of the lymphoma"'- The fact that several Hf:V-unrelated splenic R-eel! did not respond lo in.lcrfcron therapy supports Lhe idPa thal the of the lymphoma is indeed caused by the elin"ination of the stirnulating antigen, rather than sen- sitivity of the lymphoma cells themselves to interferon". Foreign antigen seem.s to have an indirect role in acti- vating B- cell-lymphoma clones in gastric ~MALT lym- phomas_ Here, neady all cases arc associated with chronic infection of the gastric mucosa by the bacterium Helicobacter pylori'''. However, it is not the lymphoma cells that recognize the bacterium, butT-helper cells, which stimulate the proliferation of the lymphoma cells'"- Notably. some studies have indicated that the phoma B cells recognize autoantigen(s)"''''', and a recent analysis showed that a considerable fraction of gastric and MALT lymphomas (::Z0-10% of cases) cA.--press autoantibodies with specificity for IgG (that is, rheumatoid factors)"5 ~oreign and autoantigens therefore seem to synergize in the pathogenesis of ga.>tric 1vL\LT lyrnphmnas. Role of the lymphoma microenvironment In many lymphomas, the tumour microenvironment is likely to be important for the survival and/or proliferation of the tumour cells. fn tollicular lymphoma, the tumour cells reside and proliferate in folhcular structures in close association with T-he!per cells and follicular dendritic cells, as is typical for normal tiC E cells. Some B cells belonging to the lymphoma clone can also be found in the interfollicular areas, but these cells show lit- tle proliferative activity'". So, the lymphoma cells seem lo require lhe cellular inleraclions in the GC-like envi- ronment for their proliferation. This is supported by studies that showed that follicular lymphoma cells can proliferate in vitm cultured together v;ith CD4+ T cells, or with stromal cells and an antibody against the CD4o receptor"'"- ( IS expressed bytolhc- ular-lymphoma cells, and its activaliDn is a main sur- vival signal f{Jr normal GC B cells. Notably, it was recently shown that the survival of patients wilh follicu- Jar lymphoma is correlated vvith characteristic features ofnon-tunumr cells in the lynrhoma ti,stJe92. So, it seems that follicular lymphoma cells retain key features of normal GC B cells, including the dependency on BCR expression and activation, as well as the interaction >'>'ith T cells and follicular dendritic cells in the follicular microenvironment. Low-grade gastric MAIT lymphomas also depend on the interaction with tumour-infiltrating T cells. These lymphomas are closely associated with H. pylori infection. In vitro, H. pylori stimulates Lhe proliferation of tumour- infiltrating T cells, hut not of the lymphoma B cells directly""- These T cells then provide contact- dependent help to promote the survival and prolifera- tion of the lymphoma cells"'. The fact that elimination of H. pylori by antibiotic treatment often le:.~ds to regres- sion of the lymphoma highlights the importance of this interaction in lymphoma progression81 fn B-CU., tbe leukaemic cells in the peripheral blood show very little proliferative activity, indicating that the expansion of the tumour clone migbt take place in other ti-;-;ues affnted the lymphoma. 1nJeed, era lion ofB-CLL cells is largely reslricted lo prolifer<l- lion centres in lymph nodes and bone marrow, where the cells are in intim:.~te conlact with CD4 T cells and dendritic cells93 The in vitro survival ofB-CLL cells can be significantly extended by culturing the leukaemic cells with stromal cells, and B-CLL cell proliferation can be induced by triggering the CD40 rcccptm94 9s. },s cDJoL is expressed by a fraction ofT cells in the proliferation centres"', it is intriguing to speculate that the T cell- B-CLL interaction in that particular Inicroenvironment provides important survival and proliferation signals for the malignant done. Histological of classical Hodgkin's lym- phoma cells have also indicated an important role of the cellular microenvironment in the pathDgenesis of this B-cell malignancy. The HRS cells usually account for less than 1% of cells in the tumour tissue, and most ot the cellular infiltrate is composed ofT cells, eosinophils, nucrophages, B cells, plasrna cells and other cells. }\!though this cellular infiltrate could partly represent an (unsucce:>sful) inl1amma lory response againsl lhe HRS cells, there is evidence that at least a large fraction of the non-tumour cells is actively attracted by the HRS cells. For HRS cells attract CD4+ T cells by the secre- tion oflarge amounts of the cytokine (thymus and activation-regulated chemokine), which is normally only e:A--pressed by dendritic cells"'- Indeed, HRS cells ~An;Rt: ]{EVrEws 1 cANCER 2005 Nature Publishing Group VOUif\lE 5 I APRIL 2005 I 259 CGU BEN0000251 R CDW C:o-sliH1UlaiOlJlliOkGllC expr~ssc:d on B celk ~nte:-acl<> 'Nith ligcm <Is expr..:sscd by T cells. ClJbD (~o- stin1ula~uryn1ol.fculc n~alnly t>X-prc:.:;.:;~,t nn ;:.J.._-_hv;rtf'd R -~.- dl~ Tntcracts 1-vith ligands express<:..:I byT cells are usually in direct contact with T-helper cells. Importantly, alchough I IRS cells have lost expression of nwst B-cell-spedfic geues, nwlecules irnpurtant for interaction with T-hdper cells (major hislocornpalibility complex class IJ, CD40, cnsJ and C')B.S) are still expressedr, indicating that this interaction with CD4' T cells is important for the survival of the HRS cells. The dependency ofHRS cells on their ty1"ical rnicmcnvironrncnt is further supported by the difficulty of maintaining these cells in culture, by the inability of primary HRS cells to survive in immunodeficient mice, and the observation that HRS cells only rarely disseminate to the peripheral blood'~. Implications and future directions In an emerging picture of B-cell malignancy, tumour progression not only depends on transforming events, such as chromosomal translocations, but also on survival signals mediated by the expression of a ft:nctional BCR and cellular intcmction;, in the lymphoma micmenvironrnent. Tn many lymphomas, BCR binding of foreign or autoantigens to stimulate proliferation might also be involved. Other than pathogen-derived antigens that cauS~e chronic infections, certain oHJtoantigens can also slin-mlate reactive B cells. This concept is also supported the observation that several autoim- are commonly associated with an increased risk oflymphoma'3,q9 Moreover, autoantigen specificity for the BCR expressed by the lymphoma has been reported for some patients with autoimmune disease who developed lyn<phoma""'. Hm->TVn, it could be that in some cases, antigen adivalion provides a chroniL prolifera!ivt> slinmlus loB cells lhal only increases Lheir risk of malignant transformation, and that antigen activation does not have an irnportant role in progression of established lyrnphomas. Tl1e finding that rnany lyn1phorna,; seern to arise tiom B-.:ell precursors that were 'frozen' at a particular stage of differentiation could reflect key features oflymphoma pathogenesis. For example, lymphoma-associated translocations that disrupt the BCL6 gene result in con- stitutive expression of this transcription factor, keeping the cells in a proliferative. GC B-cdl-like stage. and pie- vents their diilerenliation inlo a resting posl-GC B-eell stage. The dependency oflymphomas on BCR expres- sion, antigen triggering and microenvironmental sur- vival signals might contribute to the relatively close similarity between many B-celllymphomas and their nonnal B-cdl counterparts in terms ofphenotype and gene-expression pattern. The dependency on such fac- tors would select for a tumour phenotype that still resernbles nornral B cells in many aspects. ln other instances, if the transforn:ring events release the cells from ~uch a dependency, the lyrnphoma cell' would he free to acquire a markedly different phenotype. This might be best exemplit1ed in classical Hodgkin's lym- phoma, where the BCR-deficient HRS cells have lost most features of normal B cells. Can new treatment options for B-celllymphomas be developed from our current undnstanding of the role of the microenvironment in lymphoma progres- sion and of antigen as the driving force for prolifera- tion of lymphoma cells? Lymphomas might he treated by unconventional approaches, such as by interfering with survival or proliferation signals from other cells in the lyrnphoma microenvironn~ent, by elirninating antigens that promote expansion of tumour cells, or by interfering with the BCR signalling pathway. The success in treating patients with II. pylori-associated gastric MALT lymphomas, or patients with HCV- associated B-cell lymphomas, by eliminating the infectious agents are the first promising .:xarnples of this approach. Finally, the gcnc-exprcs>ion profiling stutlies oflyrnphornas might reveal previously unncc- ognized mecbanii>ms o[ paLhog('ncsis in B-cdllym- that could lead to novel therapeutic strate- gies. For example, the recognition that a subtype of diffuse large B-cdllymphoma expre,ses an active NF- KB signature led to the identification of a dependency ofthese lyr:nphomas on constitutive NF-KB activity making this transcription factor an attractive target for t h e r a p y " ' 1 i. Fi~hs-r, S. :~. & Fisher, n.l. The cp:demidDgyof'lon- ~--od!=]~:n's lymphorna. One;cnene 23, U.C:2!.,-3D34 (::2CJ4). 2. J.c.lfe, E. S.. ~:Fri~, Stein, H.<$,. Vardi~'an, J. VV. 1//orfc1 t-I'.Jaftll OrganizotiO'l Ctassitication ot Tumors. Pathoiogv and Genetics ot -:urnors of Hematouo,'H!iG and I yrn,r;hn.'d Tls:s11::'s (Ads KIFdnuis, P. fi!., Sohl:1 I .) (IAiiC. Lyon, 2o:::r1). K. CID~;JJ selec11or; anrlle.aJnl~g 1n tre art hody 751-758(~996;. K. s. 6. Grca\.eS, r~,t Drrfcmnti.c.tiO'l-linkcc leuk-J'flJ;JSnesi:s II' lymphc-cyes. 5-ch3ncd 234, 6;37-704 ( 1286~. 1. Sh2ffvr A. Rusen\IIJa!cl, A. 8 Staud+, I. M.l yrnphoid rn~Ji;:,J!lctndes: tf1t Gar'< s:de of 8-,__:ell dffe~e1ti.atior1. /'J:=,.ture .,..;;ev. !rnmu.nol. 2. SJ2]-9~~2 (20D2). Al1zaceh. A. A et .a/. Dlst:'lct types o-i diffuse large B-cell lymp~f'rra. irle~t1:-oc tv ge,ne expre2.son pml:l:ng. f.Jature 403 503-511 (2CJO\ Showed thatdis1:inc1 subsets of diffuse large B-cell lymphoma can be identifed by large~scale geneG expression profiling. e: Klein, !J. etai. G'8neexpress1on praTIIing o1 B ~ell chronc; l\n I!Jhuc..:}Jtic.: leuken ic. n::'Je<..:!lt:: a hutTIUQF1eoUs phcn:Jtype r-n!Mt"'rl 'n m<=;mn.-yRr.8lls.,;. FXf>. l'v1oi. 194, lfl/"'1-ifh~fl{/Ofll). KL1ppers, H. &Ualla-f-avera, H. Mechanisms of cfiromosor:;al ~rans;locat:ons :n 8 celllyrr:rmr:mas. 20. 5580-55t.l1 (2001). 11. G. & Dver, rvl. Blood !16, 802-922 12. ,Jiiger, U. e1 ai. con-::ain ten: plated 'lucle:Jt,de insert-ons: thf; ITI'-1Lhari1Grn ofl{1..:..::Gilransl<lcnt-on. Blc,nd95, 3520-3-529 I2J8D). I~""' Tsuj:rncto, Y., Gork;J""'\ J .. Guss'nan, J .. Jalis, E. & Groce, C. t\~. Tn.c:t(14, I P) r.hrnrYJosnmf~ tr;Jnsln<::~tinns in mt,/P.O in ~-<.All 15. Goo6;:-,en:s, T., f-(1-H''l, U. & l<j~:pr:r":. r=i. Frequr:r1: cr:.:um-ence -cf deletions ancl duol:c:~tions d\..lring so:11at:c hy:Jtwmutation: mp!iccti:.>nt; fur cncogenc: trant;!uc.:ctiotls and ht:a\V d:ait: -r;:se~~P.. pr;y_ !V;;:;tl fir:r~d. Sd. u.~A 95. ?.J.fi,~-/4fi?. C1qSJP). 16. 8nJss. L. et ::::11. UNAdcubls-stranc: breaKs 1r1 .;om-;llt.: hvGer~u:a.IIDn. ~enes. .'va'ure 403 2 1&-221 (2000). 10. L. eta'. Hyp-sr!~,J~atinr; dmul::!']leprol:o- -cnco.:;enes in 1.::-.::,ell drtiu~e latqe-celllyrnphonlas. Natu1=: 412, A1-:l~c (2:1C1). Showed that multiple proto-oncogenes are targeted by somatic hypermutation specifk:ally in diffuse large B~cell lymphomas, which could have .a majnr role in the pathogenesis of this lymphoma. ~~~- S.C., S\vanson, f). C., 'J'Ju, X., c-Jsmh, C. L. & I I260 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000252 R ws ~U. 1-l:-om, K., ~v1e!ek, t\-1. 8.. Gellen:, 1\/l. UNA trOJ.r:sposl"::ion by the HP,G: ?fl-rl H/\G2 pro:RPls: a pos.::.1ole source of onc:Jgen1c tralskx::at--cns. Ccl/94, -<1 E3-1-70 21. P.cU-,_ atransposase 22. ;;;::~. Pa.~,qddii..ICC:, L. dt a/. SCL-5 :mJatiCJ' 1<-'> in nmrnd !dVn::inai center B c;-ells: ev:denr:;-e of so~atk:; nypermJ~at::::Jn aciing ou:sid-e lg loci. Proc:. f'J.A!i/'l.cad. Sci. USA 95. I :816-i 132' (1998). ::4. norma! G cells by the proc-ess -of sor-atic 'YI-""'"'"'n.. u c:.f lg -;~ene~. Sde'lG'1280. :::5. Gr'J~haek, <. etfJ!. Somatlf' Fas mutctons n rcn-f-b~gkin's lyr1phoma: ass<Jcatior w,th extror-odc.l d:sease and au.-oimrnLnitt- Blcod 92. :3CI El-::~D24 (I ~9<-JJ. 25. E:.sser. C. & Radb-u~n, ,6,, lrnrnurlOglobulin cl<:1ss swilching moler.LIIar ann cellular Cinalys:s. 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References 48 and 49 show that the EBV..enGoded l.MP2A <::an repla<::e ihe1unction of the BCR in murine B c;ells. SO. Sch\il.'enr:g, I. eta!. :...c-ss o( the B-!:n~;;;ge-sr~JE_:;cf:c ~ene exp:ession program in Hcogk:n ord Heea--st-ernoerg cslls d r---odgkin lir<:P'lDma. Bico:/101 I hO.".l-1!::1: 2 (:!OJ,~). 5 i. /U. Sthoeger, Z. M. eta'. Production ct auLoa'lt-bn::l:e.s by C~b exp,ess:ng lymp~OC'ftes !to'l' nat;en~s wrth chro'liC lymphccyt:c 1-eL:kerris.. ,_}, Exp. r14ed. 169, 235-:.::62 ~1939). 7i. ~kmr, D. L. en!. HT~V- 1 -a:Ssco;:t-ec:' B-eall C:....L: 'ldired ~<:1le +m ~ett:Jv:rus in teukemogenesi.s. Science 236. 1j 03-1103 72. r m:, r. et al, ChroniC !ympr:{;cyliG leukeml2. G c.-ell~ eXO'fl'SS re:st,l<: ted ser::: qfrn~,tatc-;d arc ,Jr:r:rutB~ecJ ,:mtigel-, r~cept1 n:::,. '-' ln11esl. 102. 1515-1-525(j998). 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K::opos:'s sa.""ccma-8SSCC12.l-2d h<:=!T2S \:ir.Js c:J.rC asq.rred itr."lUn'Jdefici~'lC) relatej Semi/""!. Or,~o/, 27, 1DQ--'1 essential br t~e :::urv,val ::r; Infected lymphoma cells. J. E.xp. l1A;d. 199. SlB:J--1 OJ:::l (20~14 ). 00. ~(taus, rvt. ,AJ.mzrlanov, rv1. 6., Ra::ew~ky, N. & Ra.jev-vsk.v, K. aS1 Jr'/ivfJ :11 r~5llng mc.;\_n=~ lymphocytes rlepe~d.s cr: BCR s1gnalin~ via ~h-8lga:,'C het-':!rodimer. Gel( i 17, 787-800 (2CJC14'). ~.LJ. Len, K:.. f-.:, KL:hr, -=-{_ & Raj-':?Wsky, K. in VIVo zblatrun DT surface immLPlDfliJt'-tll''l en !T1atu--e t2'gt=-Ung te;olJts r-, ~3pi-~ ce:! deat~1. Ce/f 00, In references 33 and 34 mouse models were generated that provided strong evidence that normal mature B cells strictly depend on BCR expression and signalling for slJrvival. 2.1'-i. Gurv.J!l, F!, Kl-.;irr, Nc:irr, E.. N-.Jrin, T. 8.. Sir:{,df:, S. '3,Jrfau-~ irT:rnurnylob_:lins on Burk ~l'2: l},rnoclJrna biopsy c-ells lrorTI 91 pati:=:;nts. Int. .J. Cancer 25, ll i -I- 9 il98fJ). ;-::.n. SR(F-'ll, C"-i Gnncqr rit..wt dPiiriP;-Jtlnn nf <ii rrfnc"C lq. E3- cell dtiierent~1tor anti~ens, and HUUI~ Jn lymr;hdd prDiite>-ations t_:s)..-g tf,~ee-c-olur ,rnmU"I-oc.y'tcrnetry. ::3,:.G-3S9 ("'qfll). ct al. Hi:J~:JUcnc~:c cutrclaticr IS LctVv'CC~l subc:s.tc~YiC'3 of :::mull nod::-avcd c:E::IIIyn-:nhot-:la:'l. Blood 79, 1262-1290(1982). 38. de ..Jonq, D. -ct a!. Tr.ansloca::otl t{l4:: 8'1 i~ 6 cdllymph-cmo;:.s as 21 G:tuse (or d~lecli\'c8 .~nrrl-.Jnuglcbulir~ p<Joucliun. J Exp. /"vied. 169, 6 3-624 ( 1989). :,~. Cl8.1!;!, M.L.. '-""'"'!!.Cit 1slP-ring nf R).tAnsivA.<:cnr~tic rTilJt''lt-nn-~: in rilevmi"bl{'; rpgicn ot a1 immLloglct--ulin heavy chn1r Q-PnA from a r1urnan S celllymphcrn<:.~. Ce/144, 97--1 CJE 11 986). 40. MeO:!k:G'. T. ei d!. ~mergenc-e- of idiotypo variants dtJ'in~ tre21trnent of 3-:]ell anti-idic~}-~8 ..:.;ntibod::~-s. N. 4-j_ ::::-elisin l}:n1ph1..xyt::o r;redomiranl n:>f-::rBsent ::;lanai 1--JUU.Jb.tiun~ uf wcm ::r d cerlhor-ueri\~-J tur .._)r B (.,elb. Fruc. 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Down-regula::::Ul ct 806.1/0Bf~! and C:.;t2 in d:::,~<:;ir:11 rlnr:g:-:l rll:o:;P<'!<:P hut rot :n l~'mrl,nc::,tn prs-::J._oninal't f-bj~~klr 55. lfuLes:-:.e:-:.. Eut. v'. !i llfnUr 10/. 33, '592~ j 6=:2 (2D03). S6. Ca~,-t-.1k.J, C. t.-.'1 rvuk~cular i 1i~n-'1d'---~' 1~--~'=>i~ u~ f-Ju~_,ttr;m::::pl.dllt lyrnphcprd1er3tiJe di.sarc:lers. Blood "'102.3?'75-21785 (20021. b f. Trnms, ,J. M. ol a!. Target cell~ of Epstein-Ba.rr-vitu:s :EB'J> r.:.-c.)s tt'Je r~:Jst-transplar1t lyn1ph<.:.lproliter ati\e J1sease: sitT:tl8.ri:ies to E-RV-posiLIVB H:Jdgkin's !ymphcmz. Lan::el 361. ~ 17-:::'~8 bE,. aG\Nity are prevalent ir~ rn:::dia0tin::~i 0-cell :yrnphonra. Blood 98, ?1~?-)i?O(::?DOI; 59. Pilei. S. A. ei.a!. Primary rr:ediaslhal 8-.Ajlll::;n:r.JF~mna: h.gh freqt~cncy o( SCL-6 mL.r.at:ons arcJ c_,cr-<sis:e(lt c>::prcssio~ o( 1r.o tr;.;r'1sr.ript1on f?J--:to-:=; OCT-?, AnR. ', r1nd Pl :. h the :~n.-=.:f'!nn~ o~ IHTHl;~ghbUI"T;;;. Am. . I. R:J"l.I"JC!. 152, 74.'4-:?1..,:-:JQm'<) -60. Rttz. 0. 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H., Cloning d I:Jcl-0, the lu=:;~ls ,.l chtomosorr:e translocfl~ons 21tfectin bane ~Jq27 .n B-c5lllymp:c~a. Ca.'IC3f He.s. 53, 27,32-2731J f1 B9S;. I 17. Vli'di6'S. L. IV., \'Vwnf<t::, R. A., Sklar, J ..~ Cledl\', M. L. MolcG.IIar cna:vs:s a:' tf1e :(14;18) c'lrcn:osomal transloca.~:un in rn<:~!i~::Jnctn': lyrnphor-r~as. l\1. Engl. J. /lied. 317, 118. rece>,nn,mren and ~rans!ocat1ons ::ellly,...,phomas. Ri-::;od m~Jts.ti:w,s a~c as~1ociatcd -Nith ir~.act:'mtion of the ARF-TPE3 ~~1rn::w .suppressor p.athwa.;' n rlif!\JSB lag-f.: 3-cell lymphoma. 5/nod1 00, i L~~~t-14~!7 (2002]. 1~0. kud..Jru, P. rl.. Curreldt:cn belw~ rnutat:cr :n p53, p53 expression, cym-gono:cs. histologic type< ar:d :::urviva! pati-e~ :ts with 8-cell non+lodd-<in.s lyry1pl":onn. Blouo 00, 1::C 1. l\1o11H. ~v1. 8. et 3!. L\uerrat1uns c,f the p!:>~\ pathwcy compcn<?.1ts r/<J. rvu~;v12 a'ld ClJKN2A app-'3'ar ir-dcpe"'dent n drFf...:sel.arg2 B -cr::l! tyrrpho'"Yl8. Leukemia 13, /S3-r159 1~~- Mcl2ncr, 8:.allcl:-c m~_;tatiol d SCCS-1 imp:.1im JA:<? IUo!OillhJf''"" 3G";ron rn MeCB-1 105, 2E<JEr2~)42 (2DC4). son:a::ic: :-~ypermuta~:on in pnm.c.,y rrttdir:J.<">i.lr,:tllar<;Jf.: B<k:l: l;rnr:JfFJrna_ B-'~Rx.l 1-04., A.2.2t)8 (2QQir]. I ~4. Dall.a-FaJera. R l\1ar:nottL S., Gallo, P. C .. Erikson, J. & t ;ror::P, C. f\11. Tr;::Jns!nc;;;;thn ;;,n;-l n;;::Jrr;;;;noA:-rBntc:: nf th.~ e-n lye on,~uget~-e loc'-1;;,: in hurr:an ~..;ndl:ftfH t1a~e:.:.i 8-cell 1'-,r'flrhoma~. Scrence :219 983-9f7 {1983), 125. la:Jb, R. et a,1, frat'slc::::ati-on -of the ::::-myc -gere into the irmr.uno::Jiobulirr f1ea.vy d:aw' !cc~B in r~um:-.:;n Buk:t:: s:1d mLJrirlC Pre c. F\iatl 12G. relaced qens F-182//J 13C 1clen~ify d-:'tE:ret-t p:::c-c~enetlc fTieCJl-Etll5fl15 in acJd amor:g But-<:.::lr_'s 1~-rnpr~ornJ. {-:.-.Ji:Jt:,rJeS. Arn. J. Fathol. 156. 751-750 (2JOO). 127. Cotarmes, E., Khan, G., Aillet, F.. ,_:drrett. R. F. 8. rlay. R. 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Avc:-L:JiseaoJ, H.et~l. 1;H)(~13q32) ivl j.JJ.~'er-ts v~.Jilh 58. Sfi4}-SB4S r::ultip:e tnjelot-1a :,:; as.sociated v\it:l 9Xptes.slor 'df.itl1J llll.ftdt:{X';:, u"il:.rvlJI.::~~t !:Jr..:nJlll f.-.K.tu~ re-Lt~tur 3. Nature Genet. 16. 26D-:?54 :-1 98"?':. 146. Ght:si, M. et .a!. FreqJent Uv.sregul:::;tiur~ utthe c-.r11af prntc.-ni~CClQP.nF ihq/?, [r_:onsl:~;-;~tinn tc. lg locus :n tnultlpl~ myeloma. B1cod 91, !',..4b f-LIL1D:.:', (~ 'dld3). 1-"8. i4~. LIL. P :::t 11/. r\ctiva.tit IQ rnl!tdtiOil'i !"'J- and K-rds in :-nuitlpie myeloma sc:ovv different -clin:cal associations analysi;:: of tho Eoste'"l Gcuperctive 0'"1C:Jiugy' Gruuw ::::.'ldse Ill T~ial. B..uod 88, /h~N-7"/flfi (: q~lh; I!:JO. Kuehl, VJ. M. & De~Qs.'.4.;;jel, R L. 1\1ultlple rnyelon1.<1.: e,Julvin;; compotirlJ financial it:terests. DATABASES The following term-s in this article are linked online to: Enirez Gene: h'ip:!Nvww. ncO:. nlr--. nih. aov/entn.:=z/-query. fc.qi?db=wet :t:: BCL2 BCL6 BOB1 I I IPL.I em-DB 1 ccn5l I IP5.J National Cancer Institute: arthcits I FURTHER INFORMATION Lymphoma/leukemia Molecular Pro1iling Proj-ect: ht;p: l~lmpp.n h. gG\ :lyrcp:lon-a Access to this interactive links box is free cmline.. I I262 APRll 20G5 VOlUME' 5 2005 Nature Publishing Group wwwgnature.comj reviews/ cancer CGU BEN0000254