Review

The Pax-5 Gene: A Pluripotent Regulator of B-cellDifferentiation and Cancer Disease

Pierre O'Brien1,2, Pier Morin Jr1, Rodney J. Ouellette1,2, and Gilles A. Robichaud1,2

AbstractThe Pax-5 oncogene encodes a potent transcription factor that plays a key role in B-cell development and

cancerous processes. In normal B-lymphopoiesis, Pax-5 accomplishes a dual function by activating B-cellcommitment genes while concomitantly repressing non–B-lineage genes. Given the pivotal importance ofPax-5–mediated processes in B-cell development, an aberrant regulation ofPax5 expression has consistently beenassociated with B-cell cancers, namely, lymphoma and lymphocytic leukemias. More recently, Pax-5 geneexpression has been proposed to influence carcinogenic events in tissues of nonlymphoid origin by promotingcell growth and survival. However, in other cases, Pax-5 products have opposing effects on proliferative activity,thus redefining its generally accepted role as an oncogene in cancer. In this review, we attempt to summarizerecent findings about the function and regulation of Pax-5 gene products in B-cell development and relatedcancers. In addition, we present new findings that highlight the pleiotropic effects of Pax-5 activity in a numberof other cancer types. Cancer Res; 71(24); 7345–50. �2011 AACR.

Introduction

Pax-5, or B-cell–specific activator protein, was initially char-acterized in the context of B-cell commitment, where it wasshown to be essential for B-cell maturation beyond the earlypro-B stage (1). Recent developments have led to the identi-ficationofPax-5 expression in several non–B-cell cancers and toa better understanding of the upstream activators and down-stream effectors that revolve around this transcription factor.We begin this review with an emphasis on malignant diseasesother than B-cell–derived malignancies in which Pax-5 hasbeen shown to be deregulated. Subsequently, wedescribe thekey factors that activate, interact with, or are transcriptionallyregulated by Pax-5, and we highlight how these interactions areimportant for tumor formation and metastasis.

Pax-5 in Development and Cancer

Role of Pax-5 in developmentThe paired box (Pax) genes encode for a family of develop-

mentally regulated transcription factors that serve centralfunctions in cell differentiation and tissue development (2).Pax-5 is required for B-cell commitment, as evidenced by themaintenance of pluripotency observed in Pax-5–deficient pro-B cells (1). Additionally, Pax-5 ensures the maintenance of B-

cell identity during subsequent differentiation. At the onset ofB lymphopoiesis, Pax-5 repressors are overcome by early B-cellfactor-1 (EBF-1)–mediated chromatin remodeling, which ulti-mately activates Pax-5 expression and initiates B-cell commit-ment (3). Pax-5 is initially expressed at a pro-B stage and ismaintained until plasma cell differentiation occurs, duringwhich time it activates the transcription of genes belongingto the pre–B-cell receptor signaling network as well as a seriesof secondary transcription factors that further strengthen thecommitment to the B-cell lineage (4, 5). Concomitantly, Pax-5also represses B-cell lineage–inappropriate genes (4). Pax-5 isthus considered as a central regulator of the B-cell geneexpression program.

In addition to its role in B cells, Pax-5 has been linked to thedevelopment of other tissue types. During mouse embryogen-esis, Pax-5 expression is observed in the mesencephalon andthe spinal cord (2). Accordingly, Pax-5 null mice have alteredmorphogenesis of the midbrain. In this context, Pfeffer andcolleagues (6) showed that Pax-5 expression is activated bystructurally related Pax-2 and other homeodomain proteinsthrough direct binding of an enhancer sequence within thePax-5 gene. They also showed that Pax-5 was expressed in aspecific temporal and spatial pattern during the formation ofthemidbrain–hindbrain boundary of transgenicmouse embry-os, which is an essential step preceding the development of themidbrain and cerebellum in the vertebrate embryo.

Pax-5 transcription is regulated through the activation of 2known alternative promoters. This generates transcripts withdistinct first exons, 1A and 1B, with otherwise identical in-frame sequences. Moreover, alternative splicing eventsthroughout the transcript generate multiple protein isoforms(7). However, due to the inherent challenges of isoform variantanalysis, not much is known about the contribution of thePax-5 variant proteins in normal and cancerous contexts. As a

Authors' Affiliations: 1D�epartement de Chimie et Biochimie, Universit�e deMoncton; 2Atlantic Cancer Research Institute, Moncton, New Brunswick,Canada

Corresponding Author:Gilles A. Robichaud, Faculty of Science, RoomA-212, Universit�e de Moncton, Moncton, NB E1A 3E9, Canada. Phone: 506-858-4320; Fax: 506-858-4541; E-mail: gilles.robichaud@umoncton.ca

doi: 10.1158/0008-5472.CAN-11-1874

�2011 American Association for Cancer Research.

CancerResearch

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result, their respective functional significance is poorly under-stood. However, recent studies have begun to shed light on theexpression of Pax-5 protein variants as well as their putativefunction in both normal and malignant B cells, as discussedfurther below.

Pax-5 in B-cell malignanciesGiven its pivotal regulatory function in B-cell development,

Pax-5 can be considered an attractive candidate for involve-ment in B-cell oncogenesis, and accordingly, its aberrantexpression is correlated with aggressive subsets of B-cellnon-Hodgkin lymphoma (8). Furthermore, in lymphoplasmo-cytoid lymphoma, the Pax-5 gene is often implicated in arecurrent chromosomal rearrangement that places most ofthe protein coding sequences under transcriptional control ofthe potent promoters of the immunoglobulin heavy chain (IgH)gene leading to elevated Pax-5 transcription (9). To gainknowledge about Pax-5 chromosomal translocations in humantumors, Souabni and colleagues (10) reconstructed a human t(9;14) translocation in a germline mutant knockin mouse byinserting a Pax-5 minigene into the IgH locus (IgHP5ki).Consequently, forced Pax-5 expression in the hematopoieticlineage interfered with normal T-cell development, which ledto the formation of immature T-lymphoblastic lymphomas inIgHP5ki mice, suggesting that the T-lymphoid lineage is alsoparticularly sensitive to the oncogenic program of Pax-5.Although the oncogenic contributions of Pax-5 in B-cellcancerous lesions have yet to be completely elucidated, itseems that downstream perturbation of the B-cell receptorsignaling network of genes can, at least in part, account for itsrole in B lymphomagenesis (11).

Pax-5 deregulation is also associated with certain types ofacute leukemia, particularly B-cell precursor acute lympho-blastic leukemia (B-ALL). Pax-5 has been shown to be closelycorrelated with this form of leukemia and may become areliable marker for the diagnosis of this disease. Fluorescencein situ hybridization studies are revealing an increasing num-ber of chromosomal translocations involving Pax-5 in B-ALLthat result in the expression of novel chimeric proteins. Someof Pax-50s fusion partners encode themselves for transcriptionfactors, such as ETV6 (12), or encode for functionally diverseproteins, such as JAK2 tyrosine kinase (13). Thus far, in allreported Pax-5 fusions, the chimeric proteins retain the N-terminal DNA-binding domain of Pax-5; consequently, theseproteins are likely to retain the putative DNA-binding andtarget specificity, albeit with altered regulatory properties. Thisis exemplified by an ectopic expression study of the Pax-5–ETV6 fusion protein that showed that normally activated Pax-5target genes become dominantly repressed by the fusionprotein in vitro, leading to apoptotic resistance in affectedcells (14).

Although studies have shown that in some instances Pax-5genetic lesions result in expression of proteins with dominantoncogenic functions, as discussed above, other reports haveprovided evidence in support of haploinsufficiency-inducingPax-5 mutations in B-ALL. In particular, Mullighan and col-leagues (15) identified a series ofPax-5 copy number changes ina large-scale screening of genetic alterations in B-ALL patient

samples. Specifically, 57 of the 242 samples analyzed werefound to have genetic alterations resulting in loss of function ofPax-5. In contrast to a proposed tumor-promoting modelcommonly described for Pax-5, the tumor-suppressor/haploin-sufficiency model is corroborated by the works of Cobaledaand colleagues (16) and Heltemes-Harris and colleagues (17),which support Pax-5 tumor-suppressor properties in B-cellmalignancies. These dichotomous events mediated by Pax-5in cancer cells (pro-oncogenic versus tumor suppressor)appear to be context dependent. Further investigation is thusneeded to clarify what specific intracellular environment willdictate Pax-5 function in cancer processes. As will be discussedthroughout this review, dichotomous functions of Pax-5 incancer are commonly observed and are not limited to B-cellmalignancies.

Pax-5 expression in nonhematopoietic cancersPax-5 expression has also been observed in a growing num-

ber of cancers of nonhematopoietic origin. Recently, Pax-5expression has been linked to nonlymphoid cancers such asastrocytomas, medulloblastomas, neuroblastomas, oral carci-nomas, colorectal carcinomas, cervical carcinomas, bladdercarcinomas, and small-cell lung carcinomas. In most cases,Pax-5 expression correlateswith increasing diseasemalignancy.Furthermore, recentfindings have shown that Pax-5 expressionis present in breast cancer (18, 19) and is thought to be involvedin metastatic progression (20). Taken together, these resultsadd to the growing body of evidence that implicates Pax-5 acti-vity in diverse nonhematopoietic solid tumor malignancies.

Pax-5 Functions in Oncogenic Processes

Pax-5 as a driver of tumor progressionFindings suggest that Pax-5 function is associated with

hallmark cancer cell processes such as proliferation, apoptosis,and phenotype transitioning. In mouse B-cell lymphoma celllines, Pax-5 stimulates cell growth, an effect that is reversedupon pharmacologic inhibition of B-cell receptor componentsactivated by Pax-5 (11). Similarly, Pax-5 protein expressionpositively correlates with proliferation of neuroblastoma cells(21) and likely is involved in human growth hormone–inducedproliferation of breast carcinoma cells, because nuclear trans-location and activity of Pax-5 are increased upon autocrinestimulation (19). Furthermore, Pax-5 has been linked to cellsurvival, mainly through its involvement in apoptosis path-ways. Recently, it was shown that individual Pax-5 isoformsmay have specific effects in apoptosis (22). In a B-ALL cellmodel using a novel ribozyme-derived isoform–specific knock-down system, Robichaud and colleagues (22) showed that areduction of the Pax-5B isoform reduces cell viability byinducing apoptotic cell death. They also found that the lossof Pax-5B isoform expression led to an increase in Pax-5Aexpression, and they suggested an autoregulatory effectbetween the 2 distinct promoter-driven isoforms. The obser-vation of interregulating capabilities between Pax-5 variantshas also been made in murine models (23). A link betweenPax-5 expression and apoptosis was also revealed in a study ofmultiple myeloma cell lines, in which the authors found that

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Pax-5 overexpression promoted apoptosis events (24). Otherstudies suggest a growth-inhibitory function for Pax-5. Of note,Pax-5 slightly decreases proliferation rates in hepatocellularcarcinoma cell lines (25) aswell as in selected breast carcinomacell lines (18). In general, Pax-5 seems to confer a progrowtheffect in lymphoid cells and an inhibitory effect in nonlym-phoid tissues.

Dichotomous roles of Pax-5 in metastasisIn addition to its involvement in proliferation and cell fate

events, Pax-5 has been implicated in tumor metastasis. Find-ings in a neuroblastoma cell model revealed that Pax-5 over-expression led to an increase in colony formation in soft agar(21). Furthermore, Pax-5 directly activates transcription of c-Met (26), a receptor tyrosine kinase involved in cellmotility andangiogenesis in small-cell lung cancer. These results implicatePax-5 as a promoter of aggressiveness in certain cancer types.In contrast, Vidal and colleagues (18) showed that Pax-5

reduces colony formation and promotes epithelial behavior inbreast carcinoma cells. They also reported that recombinantPax-5 overexpression in invasive MDA-MB231 cells reducedmigration and motility. The same study showed that siRNA-mediated depletion of endogenous Pax-5 in MCF-7 cellsenhanced cell migration. These findings suggest that Pax-5contributes to the mesenchymal–epithelial transition, a pro-cess that is required for successful colonization of tumors tosecondary metastatic locations. Indeed, cancer cells arethought to transiently undergo phenotype transitioning toaccommodate the different stages of the metastatic process.Accordingly, mesenchymal properties are advantageous tocancer cells for extracellular matrix degradation and intrava-sation toward blood vessels, whereas an epithelial phenotypefavors metastatic tumor formation and recapitulation of pri-mary tumor characteristics. Of interest, a gene expressionmicroarray analysis revealed a 100-fold overexpression ofPax-5 in breast cancer cells that metastasized to lymph nodescompared with the primary tumor (27). Moreover, Pax-5 hasbeen shown to suppress the expression of the proinvasive focaladhesion kinase, reminiscent of the mesenchymal–epithelialtransition (20). Collectively, these findings suggest the involve-ment of Pax-5 in breast cancer and its progression tometastasis.The seemingly conflicting functions exhibited by Pax-5

appear to be highly dependent on precise cellular contextsand suggest a complex spectrum of functions for Pax-5 andpossibly its numerous isoforms in different cell backgrounds.Further studies aimed at elucidating the downstream signalingpathways regulated by Pax-5 will likely prove to be the key inunderstanding its role in cancer cells.

Pax-5 Signaling in Cancer

Upstream regulationHigh-throughput gene expression analysis has led to the

identification of various downstreamPax-5 effectors. However,the upstream signaling networks that are involved in aberrantPax-5 activity in cancer processes remain largely unidentified.Although genomic instability seems to be at the root of

aberrant Pax-5 expression in B-cell malignancies, so far notranslocations involving the Pax-5 locus have been found incharacterized small-cell lung carcinoma cell lines (26), sug-gesting an alternate mechanism for Pax-5 ectopic expression.The exploration of specific signaling events that activate Pax-5is critical for our understanding of the pathogenesis of thesecancers and may lead to the identification of potential ther-apeutic strategies aimed at targeting the Pax-5 pathway.

A recent study identified metastasis-associated protein 1(MTA1) as a regulator of Pax-5 transcription (28). Although itsrole in metastasis is unclear, MTA1 expression strongly corre-lates with invasiveness and angiogenesis in many cancers,including breast cancer. A study using chromatin immuno-precipitation revealed MTA1 binding to an enhancer sequencewithin the Pax-5 gene in MCF-7 breast carcinoma cells (28).This interaction was subsequently investigated in B-celllymphoma, where MTA1 directly induces transcription ofPax-5, an effect that is dependent on acetylation of MTA1. Ofinterest, histone acetyltransferase (HAT) p300 interacts withand acetylates Pax-5 to enhance its transcriptional activity.Taken together, these findings are consistent with an involve-ment of Pax-5 inmetastasis, and they underscore acetylation asan important posttranslational modification that regulatesPax-5 transcription and activity.

Recent evidence provides reason to suspect that the JAK2/STAT5 pathway is involved in Pax-5 regulation. One studyrevealed a STAT5 binding motif within the Pax-5 gene andshowed that phosphorylated STAT5 enhances activation of thePax-5 promoter in pre-B cells (29). Subsequently, anotherreport indicated that JAK2 activation induces DNA-bindingability and nuclear compartmentalization of Pax-5 in breastcarcinoma cells (19). Taken together, these results suggest 2means by which the JAK2/STAT5 pathway could potentiallymodulate Pax-5 activity in cancer cells: (i) through the regu-lation of Pax-5 localization and (ii) through the activation ofSTAT5-mediated transcription (Fig. 1). On the other hand,an inverse correlation between Pax-5 and STAT5 was recentlyreported by Heltemes-Harris and colleagues (17), who de-scribed a mechanism in which reduced expression of Pax-5and EBF1 synergizes with STAT5 overactivation to initiateB-ALL. A number of studies have implicated aberrant activa-tion of STAT5 in breast and hematopoietic cancers. Furtherinvestigation will help clarify the relationship between JAK2/STAT5 signaling and Pax-5, and the potential of the JAK2/STAT5 pathway as a target for inhibition.

Interacting partnersSeveral proteins have been reported to interact directly with

Pax-5. Of note, Pax-5 recruits the Ets-1 oncoprotein and en-hances its DNA-binding ability at the promoter of the mb-1gene (30). The Ets-1 protein is a transcription factor, and itsaberrant expression is associated with numerous cancers inwhich it acts to promote the transcription of genes involved intumor invasiveness and angiogenesis. Of interest, Ets-1 stimu-lates c-Met transcription (31), which is also a transcriptionaltarget of Pax-5 (ref. 26; see above). Moreover, both Ets-1 andPax-5 are expressed in astrocytomas and breast cancer celllines (18, 31). Although the physiologic relevance of the

Pleiotropic Effects of the Pax-5 Gene

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Pax-5/Ets-1 interaction has not been investigated beyondthe normal B cell, it would be of great interest to explorepossible interactions between these 2 proteins in a carcino-genic model to assess any synergistic effect that could con-tribute to oncogenesis.

The death-domain–associated protein Daxx also interactswith Pax-5 (32). Daxx localizes to both cytoplasmic and nuclearcompartments. In the former, it binds to transmembraneprotein FAS and potentiates FAS-induced apoptosis. In thelatter, it acts as a transcriptional coregulator with diversetranscription factors. A yeast 2-hybrid assay identified Daxxas a potential coregulator of Pax-5, and further analysisrevealed that it either enhanced or repressed Pax-5 transcrip-tional activity depending on the cell context (32). Further studywill help elucidate the interaction between these 2 proteinsand their effect on the transcription of downstream targets.

Pax-5 has also been shown to interact with the tumor-suppressor retinoblastoma protein (33). The hypophosphory-lated form of retinoblastoma protein interacts with Pax-5, asshown by coimmunoprecipitation experiments in B cells.Curiously, this finding was not explored in more detail, andfurther clarification of this interaction may reveal a seques-tering of active retinoblastoma protein by Pax-5, thus present-

ing a means by which Pax-5 could contribute to proliferativeevents.

An interesting link between the Pax-5 interacting proteinsdiscussed herein is that they are all elements of promyelocyticleukemia protein nuclear bodies. These dynamic nuclearstructures regulate many cellular processes, such as apoptosis,proliferation, and senescence. It is compelling to think thatPax-5 might contribute to tumorigenesis by competitivelyinterfering with key components of promyelocytic leukemiaprotein nuclear bodies and negatively influencing their tumor-suppressive properties.

Downstream targetsMany studies have aimed to identify downstream effectors

of Pax-5 that could account for its oncogenic role. Stuart andcolleagues (34) explored a possible relationship between Pax-5and p53 expression in human astrocytomas, and they observedan inverse correlation between Pax-5 mRNA and p53 expres-sion in thismalignancy. Additionally, a Pax-5 binding site existswithin the p53 transcript, and Pax-5 overexpression reducesp53 expression levels in NIH3T3mouse fibroblasts. In contrast,Pax-5 activates p53 promoter-driven luciferase in MCF-7 cells(18).

Figure 1. Novel cancer-associated signaling pathways that regulate Pax-5 expression and activity. Aberrant receptor tyrosine kinase activation by humangrowth hormone leads to activation of JAK2 and nuclear translocation of Pax-5, both of which are inhibited by AG490, a specific JAK2 inhibitor. JAK2 alsophosphorylates (P) STAT5, which induces its translocation to the nucleus, resulting in Pax-5 transcription. HAT activity is also important for Pax-5 regulationbecauseMTA1 transcriptionally activates Pax-5 upon acetylation (Ac), whereas HAT p300 acetylates Pax-5 to increase target gene transcription. Among thePax-5 target genes aremanycancer-associatedproteins, such asp53, hTERT, andmesenchymalmarkers [i.e.,matrixmetalloproteinase2 (MMP-2), vimentin,and c-Met]. The Pax-5–mediated transcriptional control of these target genes is highly dependent on cellular context and is discussed throughout this review.

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Recently, telomerase reverse transcriptase (hTERT) wasidentified as a Pax-5 transcriptional target (35). The hTERTgene encodes for the catalytic subunit of the telomeraseenzyme and is the limiting factor for its activity. Telomerasereverse transcriptase expression is inactivated in differentiatedsomatic cells, but it is restored in many immortalized tumorcells. Of interest, it was shown that Pax-5 directly activateshTERT transcription in a Burkitt lymphoma cell line throughbinding of a Pax-5 consensus sequence within the first exon ofthe hTERT gene (35). Thisfinding suggests an additionalmeansby which Pax-5 could enhance cell survival in cancer.Large-scale microarray studies have enabled the identifica-

tion of many Pax-5 activated and repressed target genesinvolved in a variety of biologic processes not commonlyascribed to Pax-5 function. For example, Schebesta and col-leagues (36) found that Pax-5 modulates the transcription ofgenes involved in migration and adhesion in B cells. MurinePax-5–positive pro-B cells have decreased migration andincreased adhesion comparedwith Pax-5�/� pro-B cells. Thesefindings are consistent with the observations of Vidal andcolleagues (18) discussed above, and they present specifictarget genes through the modulation of which Pax-5 maymanifest phenotypic transitioning in metastasis. The latterstudy also demonstrates the effect of Pax-5 on mesenchymalmarker expression. In MCF-7 cells, Pax-5 decreases MMP-2,vimentin, and fibronectin transcript levels. Moreover, immu-nostaining of tumor sections reveals that Pax-5 promotes thelocalization of b-catenin to the site of cell–cell contact, thusincreasing adhesion at intercellular junctions.Pridans and colleagues (37) identified a series of Pax-5–

modulated target genes with functions in cell motility andadhesion in B cells. Their data revealed the repression of anadhesion molecule, Embigin, by Pax-5. This finding is in slightcontrast to the reports mentioned above, which support aproadhesion function for Pax-5. Similarly, Pax-5 activatestranscription of a potent promotility oncogene in small-celllung cancer cells (26). These are clear illustrations of how Pax-5can stimulate the transcription of genes with opposing cellularactivities in a context-dependent fashion.The complexity of Pax-5 signaling is increased at many

levels. First is the expression of multiple Pax-5 protein variantsthrough alternative splicing events. Numerous studies haveshown that many of the Pax-5 isoformsmaintain DNA-bindingability but have different or truncated regulatory domains (7).Consequently, expressed alternatively spliced variants of thePax-5 gene have the ability to alter the transactivationalpotential of the target gene's expression. These findings under-score the importance of establishing the identity of the Pax-5

isoform and the ratios present in cells when attempting tounderstand Pax-5 pathways. Another determining factor is thecellular environment. Many of the conflicting results discussedherein are likely due to the cellular environment and itsfunctions where Pax-5 is expressed. In this context, a recentstudy revealed that Pax-5 overexpression leads to an increaseof CD19 transcription in B-AML cell lines but not in epithelialcells, where the chromatin of the CD19 promoter is inacces-sible (38). Collectively, these findings might provide someinsight intowhy such functional variability of Pax-5 is observedamong different cell types, aswell as offer promising avenues ofresearch that could ultimately lead to the development oftherapeutic interventions.

Conclusions

Pax-5 is recognized as an important contributor to normalhematopoiesis and organogenesis in complex organisms. Fur-thermore, the involvement of Pax-5 in B-cell cancers and othermalignant diseases is generally accepted. However, muchremains to be elucidated with regard to its precise functionin all cancer types. The role of Pax-5 in themetastatic process isone such example that will likely garner strong interest in thefuture. At the molecular level, knowledge about the upstreampathways that influence Pax-5 expression and its subsequentdownstream targets will not only lead to a better understand-ing of the complex role of Pax-5 and other Pax-related genesbut also provide significant insight into the molecular biologyof cancer. The involvement of Pax-5 in signaling cascades (e.g.,Jak/STAT) and chromatin remodeling components (e.g.,MTA1) sheds light on the lesser-known epigenetic functionsassociated with this transcription factor (25, 37) and mayeventually lead to promising new strategies for cancer therapy.Overall, the interesting research avenues currently under studywill help clarify the multiple roles of Pax-5.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Grant Support

Atlantic Innovation Foundation (R.J. Ouellette); New Brunswick Inno-vation Foundation and Beatrice Hunter Cancer Research Institute (G.A.Robichaud and P.J. Morin); Canadian Institutes of Health Research (NewInvestigator award to G.A. Robichaud and graduate student scholarship toP. O'Brien).

Received June 2, 2010; revised August 9, 2011; accepted August 11, 2011;published OnlineFirst November 29, 2011.

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