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Originally published online as doi:10.1189/jlb.1103554 on February 24, 2004

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(Journal of Leukocyte Biology. 2004;75:973-981.)
© 2004 by Society for Leukocyte Biology

The roles of transcription factors in B lymphocyte commitment, development, and transformation

Emma Smith and Mikael Sigvardsson1

Department for Hematopoietic Stemcellbiology, Stemcell Center, Lund University, Sweden

1 Correspondence: Department for Hematopoietic Stemcellbiology, Stemcell Center, Lund University, BMC B12, 221 84, Lund, Sweden. E-mail: Mikael.Sigvardsson{at}stemcell.lu.se


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ABSTRACT
 
Studies of normal blood cell development and malignant transformation of hematopoietic cells have shown that the correctly regulated expression of stage- and lineage-specific genes is a key issue in hematopoiesis. Experiments in transgenic mice have defined a number of transcription factors such as SCL/Tal, core-binding factor/acute myeloid leukemia, and c-myb, all crucial for the establishment of definitive hematopoiesis and development of all blood cell lineages. Other regulators such as IKAROS, E47/E2A, early B cell factor, Sox-4, and B cell-specific activator protein (Pax-5) appear crucial, more or less selectively, for B lymphopoiesis, allowing for detailed analysis of the development of this lineage. In addition, several of these transcription factors are found translocated in human tumors, often resulting in aberrant gene expression or production of modified proteins. This article concerns the role of transcription factors in B lymphoid development with special focus on lineage initiation and commitment events but also to some extent on the roles of transcription factors in human B lymphoid malignancies.

Key Words: hematopoietic cells • early B cell factor • B cell-specific activator protein • E2A • B lineage malignancies


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HALLMARKS OF B LYMPHOCYTE DEVELOPMENT
 
The pluripotent hematopoietic stem cell (HSC) gives rise to all mature cell types in the blood (lymphoid, myeloid, and erythroid) by differentiating through intermediate stage progenitor cells displaying a progressive restriction in multilineage potential [1 ]. The understanding of the processes regulating the differentiation of a HSC into a mature immunoglobulin (Ig)-secreting plasma cell has increased during recent years, making it possible to use this pathway as a model system for cell development. B cell development in mouse and humans has been extensively reviewed [1 2 3 ] (Fig. 1 ), and the following section will just briefly mention defined stages of B cell development and functional roles of some of the proteins produced at specific times in development.



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  		Figure 1. Hallmarks in B cell development. Gene expression patterns for some of the genes discussed in early B cell development are indicated by red dotted lines. The recombination status of the Ig genes is indicted within the circles representing cells. The figure also displays the pre-B and B cell receptor and the components of these complexes on the surface of the cell. V–D–J, Variable diverse joining; EBF, early B cell factor; BSAP, B cell-specific activator protein; LEF-1, lymphocyte enhancer factor-1; Tdt, terminal deoxynucleotidyl transferase; Rag, recombination activating gene.

An apparently common feature between man and mouse is the need for the pre-B cell receptor, composed of the newly rearranged Ig heavy chain and surrogate light chains, to allow the early pre-B cells to enter the late pre-B cell stage [4 ]. The ordered rearrangement process, proceeding from D–J of both alleles to V–D–J rearrangements [3 4 5 ], produces a large number of antigen-binding specificities. However, several of these newly formed genes will encode truncated proteins as a result of junctional diversity introducing frame-shift mutations or stop codons. To avoid production of immunoincompetent B cells, there exists a need to investigate whether the recombination process has generated a functional IgH gene. This is achieved by cell-surface exposure of IgH protein produced from the newly rearranged Ig gene in complexes with the surrogate light chains {lambda}5 and Vpre-B to form the pre-B cell receptor [4 ] (Fig. 1) . The complex will signal through the coreceptor molecules Ig{alpha} and Igß, encoded by the mb-1 and B29 genes, respectively, and thereby block further IgH rearrangements to prevent the formation of two functional heavy-chain genes in the same B cell [4 ]. The large dependence of the correct assembly of this complex has been supported in mouse models, as gene disruption of the IgM constant part or any of the surrogate light-chain genes results in a block of B cell development at the early pre-B cell stage [4 ]. Cells capable of displaying a pre-B cell receptor expand their numbers through a proliferative burst (Fig. 1) , where after, they initiate the recombination of the IgL genes to display a {kappa} or {lambda} light chain in complex with the IgH protein on the cell surface [4 ]. The immature B cell expresses a cell-specific surface IgM and can be selected against autoimmune specificities before it is allowed to leave the bone marrow and enter the circulation [2 , 3 ]. The newly produced cells home to secondary lymphoid organs, where they mature further into immunocompetent B cells, which after antigen encounter and T cell support, can differentiate into Ig-secreting plasma cells [6 , 7 ].

The completion of this developmental pathway, composed of several defined stages each with partly unique gene expression patterns, demands a strict regulation of transcriptional activity. This is a task achieved mainly by the concerted action of different transcription factors acting in stage- and context-dependent manners, placing these proteins in key positions during B lymphopoiesis. The main focus of this article is gene regulation at the early stages of development and modified transcription factor activities in malignant B cells. This involves initiation of the developmental pathway, lineage commitment as well as transformation. These processes have been investigated extensively, forcing us to refer to a limited number of the important contributions made to this field, and we therefore wish to apologize to those whose work is not fully cited in this article.


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ESTABLISHMENT OF A FUNCTIONAL HIERARCHY AMONG TRANSCRIPTION FACTORS IN B CELL DEVELOPMENT
 
To understand how differentiation proceeds, it is of large importance to establish the order of events and the genetic links bridging them to each other. Information about this can be based on sequential gene-expression patters, but the relevance of the data is substantially increased if functional aspects can be taken into account. The sequential need of transcription factors in B cell development has been rather well defined with regard to expression patterns (Fig. 1) and functional properties. Much information has come from studies of the biological phenotypes of mice carrying homologous disruption of transcription factor coding genes (Fig. 2 ). The transcription factors SCL-Tal, acute myeloid leukemia (AML)-1, and c-myb are all crucial for the establishment of the entire adult hematopoietic system, while the role of other factors appears to be more or less specific for the B lineage. One factor crucial for early stages of lymphopoiesis is the Zn-finger protein Ikaros [8 ]. This protein belongs to a family of transcription factors able to form homo- and heteromeric complexes expressed in stage- and tissue-specific manners during hematopoietic development [9 10 11 ]. Homologous disruption of the Ikaros-coding gene results in a complete block of B cell development and severe disturbances in the development of certain T cell populations [8 ]. The exact function of Ikaros in lymphopoiesis is still under investigation, but it appears as if the protein plays an important role in silencing genes, possibly by the participation in nuclear relocalization of chromatin into transcriptionally silent centromeric domains in the nucleus [11 , 12 ]. The Ets protein Pu.1 is also playing an important role already in the uncommitted progenitor cell [13 ], and it appears to be crucial for B cell and macrophage development [14 , 15 ]. Pu.1 has been suggested to be involved in the regulated expression of the high-affinity IL-7R on the progenitor B cell [16 ], a role possibly explaining some of the importance of this protein in early B cell development. An early block in B cell differentiation was also observed in mice carrying a disrupted E2A gene [17 , 18 ]. This gene encodes two basic HLH (bHLH) transcription factors, E12 and E47, generated by alternative splicing of the DNA-binding domain. Mice lacking the E2A gene develop apparently normal myeloid and erythroid lineages, while lymphoid development is impaired [17 , 18 ]. Some T cells develop into maturity, but the mice are prone to T cell tumor development [19 ], and they also display a lack of B-lineage cells [17 , 18 ]. No recombination events of IgH genes were detected, and little or no expression of B cell-restricted genes could be found [17 , 18 , 20 ]. A similar phenotype could be observed in mice lacking the transcription factor EBF, as their bone marrow do no not contain any D–J rearrangements or expression of pre-B cell-restricted genes [21 ]. The marrow of these mice did, however, contain cells with surface expression of CD43 and B220, indicating that they had made a lineage choice to become early pro-B cells before their developmental arrest [21 ]. Bone marrow cells from these mice also expressed sterile transcripts from the IgH locus. These transcripts do not encode any protein but are presumed to precede the rearrangement events by making the DNA accessible for the recombination machinery [2 , 3 ]. However, the cells did not express any of the Rag genes, and coordinantly, no recombination events could be detected [21 ]. Another dramatic phenotype could be observed in mice lacking the transcription factor BSAP (Pax-5) [22 , 23 ]. The bone marrow but not the fetal liver of these mice contained progenitor B cells with expression of several B-lineage genes including {lambda}5, VpreB, and mb-1, and they also contained D–J heavy chain (D–J–H) and rare V–D–J–H rearrangements [22 , 23 ]. A similar phenotype was observed in mice lacking the HMG protein Sox-4 [24 ]. However, the Sox-4-deficient pro-B cells displayed a proliferation defect in response to IL-7 that could not be observed in the absence of BSAP and that appears to be the major cause of the phenotype in the Sox-4-deficient mice [24 ]. The transition from the late pre-B cell stage into the immature B cell stage is impaired in mice double-deficient for the Pu.1-associated proteins Pip and interferon consensus sequence-binding protein (ICSBP) [25 ]. Pre-B cells from these mice display deficiencies in light-chain recombination events that might be explained by the direct activity of a Pu.1/Pip (ICSBP) complex on the {kappa} as well as {lambda} light-chain gene-enhancer elements [25 ]. The lack of these proteins could then result in reduced germ-line transcription and impaired recombination efficiency of the light-chain genes.



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  		Figure 2. Functional hierarchies among transcription factors in B cell development. The figure shows a schematic diagram over B cell development where the developmental blocks observed after that transcription factor-encoding genes are inactivated by homologous disruptions, are indicated by arrows extending from the boxes belonging to the factor. The box contains information about biochemical features of the transcription factors as well as the consensus DNA target site. Il-7 R, Interleukin-7 receptor; HLH, helix-loop-helix; HMG, high-mobility group.

Although the transgenic mouse models have produced essential information about the stage dependency of the investigated transcription factors, they still provide limited information concerning genetic networks and the links between the different stages of development. To understand this part of the process, it is crucial to identify the genes regulated by the transcription factors at each differentiation stage (Fig. 3 ). The investigations in transgenic mice described above suggest that E2A gene products are participating in the initiation and specification of the B lineage. This idea is also supported by the findings that E2A proteins are involved in the regulation of the IgH chain germ-line transcription, Rag genes, and surrogate light-chain genes in the pro-B cell [26 27 28 ]. E2A proteins also appear to activate transcription of the EBF gene [28 , 29 ], encoding a transcription factor able to activate another set of genes characteristic of the late pro-B cell to the early pre-B cell stage. In addition, EBF has the ability to act in synergy with E2A proteins in the activation of several target genes including the surrogate light-chain genes [27 ] and in Ig recombination events [30 , 31 ] (Fig. 3) . The importance of the collaborative action of E2A proteins and EBF was shown in vivo, as mice trans-heterocygote for mutations in the E2A and EBF genes displayed a much more dramatic impairment in B cell development than any of the single heterocygote mice [32 ]. In addition, EBF seems to be involved in the regulation of the mb-1 [33 ] and B29 [34 ] genes, apparently coordinating the expression of pre-B cell receptor components (Figs. 1 and 3) . The genetic network around EBF appears conserved between humans and mice, as the EBF-binding sites in the mb-1 and B29 promoters are conserved between species [35 ]. An even stronger indication for the preserved roles of EBF and E2A in human and mouse B cell development comes from studies of the genes encoding the human pre-B cell receptor components 14.1 ({lambda}5) and Vpre-B. These genes are structurally different from their mouse counterpart, and the promoter elements display a low sequence similarity. This results in the fact that the EBF- and E2A-binding sites defined in the mouse are rendered incapable to bind the transcription factors. However, the ability of the promoter elements to interact with the transcription factors remains as a result of the presence of other EBF- and E2A-binding sites rather than those found in the mouse promoters [35 , 36 ], apparently conserving them as target genes, although the primary DNA sequence has diverged. Furthermore, EBF appears to be involved in an autoregulatory loop [29 ], possibly driving differentiation of the cell that has initiated development along the B lymphoid pathway. EBF is also suggested to control the expression of BSAP/Pax-5 [32 ], which in turn regulates expression of the n-myc, Lef-1, BLNK, mb-1, Rag-2, and CD19 [37 38 39 ] genes, many of which are associated with the early pre-B cell stage. Pax-5 also appears to be crucial for the definitive lock of the cell in the B lymphoid pathway [40 ] (see below). Thus, investigations of mice carrying mutated genes and identification of genetic targets for specific transcription factors have resulted in a reasonable proposal for a functional hierarchy of transcription factors in the early stages of B cell development, where the action of E2A proteins promotes expression of EBF, which in turn allows progression into a Pax-5-dependent stage of development (Fig. 2) .



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  		Figure 3. Genetic networks in B cell development. The figure displays a model for a genetic network operating in early B cell development. Transcription factors are indicated in red, activated target genes are displayed in green, and repressed genes are in blue. The large arrow indicates increased maturity of the progenitor cells. M-CSFr, macrophage-colony stimulating factor receptor; BLNK, B-cell linker.


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TRANSCRIPTION FACTOR FUNCTION IN B-LINEAGE CHOICE AND COMMITMENT
 
In addition to the progression of the differentiation pathway, the process of lineage commitment is central in the understanding of B cell development. Although much evidence points to a crucial role for the E2A proteins in the initiation of B-lineage development, the broad expression patterns of these proteins, within and outside of the B lymphoid system [41 ], make it difficult to understand how they can be involved in a specific lineage-initiation process. The identification of a B cell-restricted E47 homodimer [17 , 42 ] led to the hypothesis that this protein complex would compose the tissue-specific component, rendering the E2A gene such an essential role in the initiation of B-lineage development. However, studies in transgenic mouse models showed that although E47 appeared crucial for normal B cell development, expression of E12 was sufficient to rescue the initial events leading to progress along the B-lineage pathway [20 ]. One explanation could be that the process is dependent of transcription-factor doses rather then a direct presence or absence of the committing factors. The concept of dose-dependent lineage choice has been suggested from studies of the Drosophila transcription factor, daughterless, belonging to the same HLH family of transcription factors as E2A gene products E12 and E47 [43 ]. Drosophila daughterless, together with other sex-determining factors, are encoded by the X-chromosome. This results in monoallelic expression in male embryos, and female embryos express twice the amount of the transcription factor, a dose difference contributing to sex determination in the embryo [44 ]. In line with this, B lymphoid development would be dependent on transcription-factor doses rather than any specific factor per se. The E2A proteins belong together with E2-2 and Heb to the E-protein family. These bHLH proteins are able to form homo- or heterodimers with each other. A functional redundancy among these proteins was elegantly shown, as B cell development in mice lacking the crucial E2A gene could be rescued by the insertion of a functional gene encoding Heb into the E2A locus [45 ]. The concept of a dose-dependent role of E-proteins was also supported by experiments, where sequential disruptions of E2-2-, Heb-, and E2A-encoding genes resulted in increasing disturbances of B cell development [46 ] and by the finding that transgenic expression of the E-protein inhibitor Id-1 resulted in impairments of early B cell development [47 ]. Another interesting aspect of the role of E2A proteins comes from the finding that the functional activity of these factors can be reduced by active Notch signaling in the cell-culture systems [48 ]. The finding becomes even more interesting, as expression of an active form of intracellular Notch in hematopoietic progenitor cells results in a dramatic reduction of B cell development, possibly in favor of T cell development [49 ]. This opens the possibility that Notch provides an instructive signal for the common lymphoid progenitor by reducing the functional activity of E-proteins, resulting in impaired B cell development. Dose-dependent functions of transcription factors have also been suggested from studies of Pu.1-transduced progenitor cells, where high expression of Pu.1 resulted in commitment into myeloid differentiation rather than B cell faith [15 ], suggesting that the initiation of B cell development well may be a result of a combined dosage of a number of transcription factors.

The question of when commitment to the B lineage actually occurs was raised by studies showing that pro-B cells from Pax-5-deficient mice were able to differentiate into other hematopoietic cell types [40 ]. These pro-B cells were able to differentiate into dendritic cells, macrophages, osteoclasts, granulocytes, and natural killer cells in vitro [40 ] as well as into T cells in vivo [50 ]. These differentiation processes were inhibited by ectopic expression of Pax-5 [40 ], suggesting that the initiation of the genetic program to become a B cell is not obligatorily linked to commitment of the cell. Furthermore, B cell clones lacking Pax-5 are able to promote long-term reconstitution of myeloid and lymphoid cells in vivo, supporting the idea that pro-B cells are highly potent hematopoietic progenitors unless restricted by Pax-5 expression [51 , 52 ]. The key role for Pax-5 in B-lineage development has now been further highlighted in transgenic mice, where the gene was rendered nonfunctional in immature [53 ] or mature [54 ] B cells, which resulted in an apparent loss of B cell identity and in an overexpression study, where the Pax-5 gene was placed under the control of the IKAROS locus [55 ]. The latter mouse model displayed expression of Pax-5 already in the bone marrow stem cell, and although the myeloid and erythroid developmental pathways appeared largely unaffected, there was a reduction in T cell numbers, a finding possibly explained by a reduced Notch-1 expression in the early progenitors [55 ]. The molecular mechanism underlying the power of Pax-5 may not reside in its ability to activate but rather to suppress gene expression. The protein has the ability to act as a repressor or as an activator, probably as a consequence of different promoter context and specific contact bases in the target DNA [56 ]. Thus, Pax-5 can display activation or repression domains, one of the latter able to interact with repressors of the Grucho family of histone deacetylases [57 ]. Genes that have been suggested to be suppressed by Pax-5 include the M-CSFR [40 ] and the Notch-1 gene [55 ]. This can allow for a formulation of a hypothesis that the crucial activity of Pax-5 is coupled to an ability to make the B cell progenitor inert to the action of lineage-instructive signals, which would drive the cells into other cell fates. Thus, it appears as if the initiation of the B lymphoid pathway stimulated by E2A proteins can be manipulated, indicating that it is not a commitment process but rather a beginning of a genetic program distancing these two processes in the course of development.


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TRANSCRIPTION FACTORS AND HUMAN B-LINEAGE MALIGNANCIES
 
In addition to their role in differentiation processes and lineage fidelity, transcription factors also contribute directly to tumor development (Table 1 ). One example is the translocation of the c-myc oncogene involved in cell-cycle regulation and apoptosis into the IgH or IgL chain locus observed in Burkitt’s lymphoma [59 ]. This leads to deregulated expression of c-myc as a result of the normal promoter and 5'-untranslated region of the mRNA becoming deleted and the gene coming under control of Ig transcriptional regulatory elements [60 , 61 ]. This results in an increased transcription rate resistant to normal feedback mechanisms as well as increased mRNA stability as a result of deletion of destabilizing elements in the noncoding 5' part of the mRNA [62 ]. The translocation could also result in an increased frequency of point mutations as a result of the action of the somatic hypermutation machinery normally operating in this region, and point mutations affecting myc function are detected [63 , 64 ]. The effect of the mutated protein may be enhanced, as the normal myc allele often becomes silenced [65 ], probably as a result of inhibitory feedback mechanisms activated by the translocated allele.


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  		Table 1. Transcription Factors Observed in B Lymphoid Lineage Malignancies

Another gene frequently involved in translocations resulting in aberrant gene expression is the transcriptional repressor BCL6 [66 , 67 ]. This gene is translocated into a position that renders it under the control of external control elements including the IgH [68 ], IgL [69 ], histone H4 [70], small G protein TTF [71 ], and heat shock protein 89a [72 ]. The noncoding part of the BCL6 gene appears to be a natural target for somatic hypermutation also in normal cells [73 ], and although the mutations normally do not result in alterations of the amino acid composition of the protein, there could be effects on translation efficiency and mRNA stability, giving the protein oncogenic properties even in the absence of translocation events.

Translocation into the Ig locus has also been reported for the transcription factor Pax-5 [74 , 75 ]. The production of this protein is normally repressed on terminal B cell differentiation [76 ], and deregulated expression could interfere with terminal differentiation [76 ], contributing to the developmental arrest observed in NHL.

Transcription factors are also reported to be involved in translocations, resulting in the formation of fusion proteins dramatically altering the structure of the factors involved. One such example is the fusion between the E2A gene and the gene encoding the homeo-box transcription factor PBX observed in childhood pre-B leukemias [77 ]. One role of the normal PBX protein is to modulate the function and DNA-binding activities of the Hox proteins [78 ], which are known to modulate hematopoiesis [79 ], and the formation of the E2A–PBX may cause alterations of Hox protein functions. One potential target gene for the E2A–PBX fusion protein is a gene encoding a wnt family growth factor [80 ]. wnt proteins have been suggested to be involved in B cell development, as homologous disruption of the transcription factor Lef-1, which via an interaction with ß-catenin transmits the wnt signal into the cell nucleus, results in B cells with impaired proliferative abilities [81 ]. The same signal-transduction pathway has also been shown to be a target for the transformation process in colon cancer, where mutations in ß-catenin or other components of the signal-transduction pathway, such as the adeno poliposis colon protein [82 , 83 ], are commonly found. Thus, increased wnt signaling could be one potential explanation for the mechanistic action of the E2A–PBX fusion protein. E2A is also involved in t(17;19) translocations, resulting in a fusion protein composed of the transactivation domains of E2A and DNA-binding/dimerization domains of the transcription factor HLF [84 , 85 ]. This HLF–E2A fusion protein is able to transform embryonic fibroblasts [86 ], possibly via induction of expression of the antiapoptotic Zn-finger transcription factor SLUG, which is presumed to be a direct target for the fusion protein [87 ].

Although the molecular understanding of the functions of fusion proteins is beginning to be unraveled, there is still much to be learned about these tumor-associated factors. For instance, a significant number of childhood leukemias carry a t(12;21) translocation, resulting in a fusion protein between the Ets family transcription factor Tel and the runt domain protein core-binding factor (AML-1) [88 89 90 ]. This fusion protein has not yet been shown to be able to transform cells by itself, but it may well act in a dominant manner in leukemia, as it will be acting in a genetic environment, lacking at least one normal allele of both proteins in the cell undergoing malignant transformation.

Another example of functional alterations of transcription factor function in oncogenesis relates to the ability of these proteins to act as tumor suppressors. One example is the p53 protein, directly involved in cell-cycle entry, which is inactivated in a large number of solid tumors and also in some cases of lymphoma [91 ]. Among the transcription factors directly involved in B cell development, the gene encoding Ikaros has been found translocated in a diffuse pattern in human cancer [92 , 93 ]. This could be an indication that the major cause of the tumorogenic effect is the disruption of the Ikaros gene itself. This idea is also supported by studies in mice, where lack of a functional Ikaros gene results in T cell lymphomas, indicating that Ikaros may have a role as a tumor-suppressor gene [8 , 94 ]. The E2A gene also appears to act as a tumor suppressor, as mice that lack this protein frequently develop T cell tumors [95 ] sensitive to reintroduction of the E2A proteins [96 ]. This could be an effect of the fact that the E2A factors are involved in cell-cycle regulation, possibly by direct activation of the p21 promoter [97 ].

Transcription factors are also playing important roles in virus-induced transformation processes. This could occur as a result of viral integrations near transcription factor-coding genes, resulting in transcriptional deregulation but also a result of direct effects of viral proteins on the transcription factor network. The Epstein Barr virus (EBV), suggested to be involved in the pathology of Burkitt’s lymphoma and Hodgkin’s disease [98 ], produces at least six proteins that display direct effects on transcriptional regulation [99 ]. EBV nuclear antigen (EBNA)-2 is a transcriptional activator crucial for the transformation of B lymphocytes [100]. The EBNA–leader protein enhances the functional activity of EBNA-2 [101 ], although the latter appears dispensable for B cell transformation [100]. The EBV genome is also encoding at least three transcriptional repressors, EBNA3A, -B, and -C, out of which EBNA3A and -3C are required for B cell transformation [102 ]. EBNA1 is also a DNA-binding protein, and although it has mainly been associated with episome replication and transcription of the viral genome, the finding that transgenic expression of the factor in B-lineage cells results in malignancies indicates that more global effects on gene regulation are exerted by this protein [103 ]. Thus, transcription factors appear able to promote malignant transformation by a number of different mechanisms, the knowledge of which could dramatically increase our understanding of oncogenic processes and possibly provide new possibilities to treatment and diagnosis of cancer.


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CONCLUDING REMARKS
 
Genetic studies in mouse models as well as findings in human malignancies have provided crucial evidence for essential and in many cases unique roles for specific transcription factors in hematopoiesis. An extensive search for genetic targets for these factors has also provided a degree of clarity about how these proteins are genetically linked and how they act to coordinate gene-expression programs, findings that well may become useful in clinical practice. There are, however, still dimensions of gene regulation that are rather poorly understood. These include the interplay between transcription factors and the nuclear organization in a specific cell type. This is important, as the structure of the chromatin is bound to largely affect the ability of a given transcription factor to activate target genes. There is also limited understanding about how cell cycle and replication affect the activity of transcription factors. Both of these aspects of gene regulation are now coming more into focus in the field of research, promising a further increased understanding of normal as well as malignant cell differentiation in the near future.


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ACKNOWLEDGEMENTS
 
Barncancer Fonden, Cancerfonden, Vetenskapsrådet, The Crafoord, Åke Wibergs, and Kocks foundations and the Medical Faculty at Lund University funded this work. We thank members of the HSC laboratory and Dr. S. Cardell for helpful comments and for critical reading of this manuscript.

Received November 11, 2003; revised January 24, 2004; accepted January 28, 2004.


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