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[Cancer Research 59, 5625-5628, November 1, 1999]
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[Cancer Research 59, 5625-5628, November 1, 1999]
© 1999 American Association for Cancer Research

Tumor Biology

B-Cell Tumorigenesis in Mice Carrying a Yeast Artificial Chromosome-based Immunoglobulin Heavy/c-myc Translocus Is Independent of the Heavy Chain Intron Enhancer (Eµ)1

Concepción Palomo, Xiangang Zou, Ian C. Nicholson, Christoph Bützler and Marianne Brüggemann2

Laboratory of Developmental Immunology, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
We have used YAC (yeast artificial chromosome) technology to create large translocation regions where the c-myc proto-oncogene is coupled to the core region of the human immunoglobulin heavy chain (IgH) locus (from VH2-5 through to C{delta}). Chimeric mice were obtained from embryonic stem cells carrying a single copy of the 240-kb IgH/c-myc translocation region. B-cell tumorigenesis occurs in the translocus mice, even when the entire Eµ intron enhancer region between the joining segments and switch µ is deleted. This demonstrates that as yet unidentified regulatory elements in the IgH locus, independent from the known enhancers, are sufficient to cause B-cell specific activation of c-myc after translocation. The phenotype of tumors from IgH/c-myc YAC transgenic mice with or without Eµ (B220+, IgM+/IgD+) is reminiscent of Burkitt’s lymphoma. A rapidly expanding abnormal B-cell population is present at birth and accumulates in bone marrow, periphery, and spleen, well before discrete tumor establishment. Molecular analysis identified a clonal origin, with rearrangement of one mouse heavy chain allele retained in tumor cells from different sites, whereas subsequent rearrangements of heavy or light chain loci can be diverse. These mice routinely develop mature B-cell tumors early in life and may provide an invaluable resource of a B-cell lymphoma model.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Many hemopoietic tumors carry chromosomal abnormalities involving the translocation and subsequent dysregulation of oncogenes. Translocation of c-myc into the IgH3 or L chain (immunoglobulin {kappa} or immunoglobulin {lambda}) locus gives rise to B-cell tumors (1) , leading to Burkitt’s Lymphomas in humans (2) and plasmacytomas in mice (3 , 4) . In most Burkitt’s lymphomas, the tumor cells harbor a reciprocal chromosomal translocation that relocates the coding exons 2 and 3 of c-myc from chromosome 8 to the IgH locus on chromosome 14. The translocation does not affect the c-myc coding region, but the expression of c-myc may be altered because of the influence of immunoglobulin locus control elements. The basis of c-myc activation is unknown, although it has been proposed that an immunoglobulin enhancer, either the intron enhancer Eµ or the downstream elements at the 3' end of the IgH locus, might be involved (5, 6, 7, 8) .

Transgenic mice bearing a minigene construct where the c-myc oncogene is linked to an immunoglobulin enhancer frequently develop B-lineage tumors when a few months old (5 , 6) . Analysis of the immunoglobulin gene rearrangements of the tumor cells suggests that tumor development can commence at several points during B-lymphocyte differentiation (5 , 9) , suggesting that the dysregulated c-myc may be active at several different developmental stages. In most naturally occurring B-cell tumors, however, the translocation event is such that the c-myc coding region is not proximal to an enhancer but is located on the reciprocal chromosome (10, 11, 12) . For example, Eµ can be either located a long distance (>100 kb) upstream of c-myc or missing altogether from the translocated region that carries the oncogene. In many of the tumors, the level of c-myc expression is similar to that in proliferating B lymphocytes (13) , suggesting that the degree of unregulated activation of c-myc resulting from the translocation may be sufficient to promote tumor formation.

We have shown recently that mice carrying c-myc linked to the core region of the human IgH locus on a 240-kb YAC but 50 kb downstream of the Eµ enhancer develop B-cell lymphomas when 8–16 weeks of age (14) . To clarify the relevance of the Eµ enhancer in tumor development, we analyzed tumorigenesis in the absence of the Eµ region. The tumors, which exhibit features of B-cell ALL, have a phenotype identical to that found when Eµ is present and arise early and develop aggressively.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Transgenic Constructs and Mouse Strains.
The E{Delta}IgH/c-myc YAC was obtained by replacing the Eµ intron enhancer of the IgH/c-myc YAC (14) by homologous recombination in yeast using a 2.3-kb homology region where the 0.8-kb HpaI-SphI fragment comprising Eµ (9 , 15) was replaced by the Saccharomyces cerevisiae HIS5 gene from pSH135 (16) . YAC-containing yeast cells were fused with HM-1 ES cells as described (17) . An 8.5-kb EcoRI-HindIII fragment of human c-myc (18) and a 10.8-kb HindIII-BamHI fragment accommodating neo/c-myc from the right YAC arm (14) were used to produce transgenic control mice. Several independently obtained HM-1 ES cell clones, each carrying the IgH/c-myc YAC or E{Delta}IgH/c-myc YAC or neo/c-myc, were injected into BALB/c blastocysts and reimplanted into foster animals as described (19) . The c-myc transgenic line was obtained by pronuclear DNA injection of oocytes (19) .

Flow Cytometry.
Single-cell suspensions were analyzed by flow cytometry (20) after staining with the following antibody conjugates: phycoerythrin-anti CD45R (B220) or phycoerythrin-anti-CD25 (Sigma Chemical Co., St. Louis, MO); FITC-antimouse {delta}, FITC-antimouse µ heavy chain, or FITC-anti-CD19 (PharMingen, San Diego, USA); and biotin-anti CD43 or biotin-anti mouse µ (PharMingen) developed with Texas Red Streptavidin (Zymed, San Francisco, CA). Three-color flow cytometry was performed using a FACScalibur (Becton Dickinson).

Southern and Northern Hybridization Analysis.
Experiments followed standard procedures (21) using the following probes: mouse 3' JH, a 0.7-kb EcoRI-XbaI fragment encompassing the mouse IgH intron enhancer (22) ; human c-myc, a 1.2-kb SmaI fragment from pUCRB19RH7 (18) comprising exon 1, intron 1, and part of exon 2 of human c-myc; GAPDH, a 250-bp HindIII-PstI fragment of the 5' end of mouse GAPDH (23) ; and mouse actin, a PCR-amplified, 540-bp fragment (see below).

PCR Amplification.
Reactions were performed with 30–200 ng of genomic DNA in 50 mM KCl, 10 mM Tris-HCl (pH 8.5), 0.5% Tween 20, 1.5 mM MgCl2, 0.2 mM deoxynucleotide triphosphate, and 0.8 mM oligonucleotides each. Conditions were 95°C for 5 min, 95°C for 1 min, 55°C for 1 min, 72°C for 1 min for 30 cycles, and 10 min at 72°C. Taq polymerase (2.5 units) was added after the first denaturation step. Oligonucleotides for mouse actin were: FOR, 5'- ATGTGGGTGACGAGGCCC-3' and REV 5'-GAGGATGCGGCAGTGGCC-3'; and for human C{delta}, FOR 5'-CCCTTCTCTGCAGGTACA-3' and REV 5'-TGTCACTTTCATCAAGGTCAG-3'.


   RESULTS AND DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Derivation of Chimeric Mice.
To study the role of the IgH core region in tumorigenesis and the possible importance of the Eµ enhancer in c-myc activation, we produced chimeric mice (coat color chimerism, 20–80%) by blastocyst injection of different ES cell clones carrying a stably integrated single copy of the IgH/c-myc YAC with or without (E{Delta}IgH/c-myc) the Eµ intron enhancer (Fig. 1)Citation . The introduced 800-bp deletion removes not only Eµ with the 279-bp enhancer core region but also a substantial amount of flanking region not implicated in the enhancer function (15) . This modified YAC was introduced into ES cells by protoplast fusion (17) , and single copy integration was verified by Southern blot and PCR (data not shown).



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  		Fig. 1. The human E{Delta}IgH/c-myc YAC. The IgH/c-myc YAC (14) contains the core region of the human IgH locus (220 kb) in germ-line configuration spanning five variable region genes (VH2-5, VH4-4, VH1-3, VH1-2, and VH6-1), the complete diversity (D) region, all joining (J) segments, and the µ and {delta} constant regions. Human c-myc and a neo-selectable marker gene were site-specifically added to the acentric YAC arm. Deletion of the Eµ enhancer removed a 0.8-kb SphI-HpaI fragment, which was replaced by HIS5. Restriction cleavage sites: Sp, SphI; Bg, BglII; Hp, HpaI; and H, HindIII.

 
Development and Phenotype of the Tumor Cells.
All translocus mice 6–20 weeks of age (18 of 18 IgH/c-mycYAC mice and 14 of 14 E{Delta}IgH/c-mycYAC mice) developed tumors in the abdomen, head, and less frequently in the chest. Splenomegaly was always observed, but lymph nodes or Peyer’s patches were not involved, and other organs such as liver, kidney, and lung were also unaffected. No tumors were observed before 6 weeks of age, and no tumor development was observed in control transgenic or chimeric mice carrying the IgH YAC (24) , c-myc (18) , or the neo/c-myc region (14) from the right YAC arm (Table 1)Citation . Cytometric analysis of the tumors showed the cells to be large B220+/CD19+, IgM+, and IgD+ lymphoblasts (Fig. 2A)Citation , which were CD25- and expressed a variable degree of CD43. This phenotype is characteristic of B cells progressing from the immature to mature differentiation stage. Contrary to our expectation, the tumors that developed in the E{Delta}IgH/c-myc YAC mice were indistinguishable from those generated in the IgH/c-myc YAC mice.


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  		Table 1 Tumor development in chimeric mice carrying the IgH/c-myc or the E{Delta}IgH/c-myc YAC

 


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  		Fig. 2. Flow cytometric analysis of lymphoid and tumor tissues. A, phenotypic characterization of abdominal tumors from 7-week-old IgH/c-myc YAC and 20- and 9-week-old E{Delta}IgH/c-myc YAC mice, confirming the presence of a population of large B220+ cells, expressing a varying amount of Cµ and C{delta}. B, presence of large B220+ cells (contribution in percentage of this abnormal population is indicated by the gate) accumulating in the spleen of E{Delta}IgH/c-myc mice, which were 1 day, 10 days, and 5 weeks old compared with control tissue from normal mice of the same age.

 
To examine the development of the tumors, tissues from animals of different ages were stained for B-cell differentiation markers and analyzed by flow cytometry. A rapidly expanding abnormal population with a phenotype similar to the tumor cells could be detected in the spleen from birth (Fig. 2B)Citation . Later, this population was also found in bone marrow and spleen, prior to tumor development, but was never seen in Peyer’s patches (Fig. 3)Citation . The distribution of this abnormal cell population as the mouse ages suggests that they are produced in the bone marrow but are unable to accumulate there. The cells migrate via the vascular system to the spleen, where they accumulate and eventually disseminate to the thymus. The circulating abnormal cells are still present when the discrete tumor mass is formed.



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  		Fig. 3. Accumulation of an abnormal B-cell population in lymphoid tissues of IgH/c-myc chimeric mice. The percentage of large B220+ cells in lymphoid organs is plotted against the age in days (10, 17) and weeks (3, 4, 5, 7, 9) of seven representative animals. (Primary data were obtained as shown in Fig. 2.Citation )

 
Tumor Cells Are of Clonal Origin.
To establish whether the increase of the mature B-cell population and subsequently early tumor establishment was the result of rapid growth of the total B-cell population or, alternatively, the expansion of a few malignant clones, we studied rearrangement of the endogenous H and L chain loci as well as the human translocus. Immunoglobulin rearrangement in spleen, blood lymphocytes, bone marrow, and tumor cells were compared by Southern blot analysis. Most remarkably, in individual mice tumors from different sites as well as tissues harboring large IgM+ cells showed that at least one mouse heavy chain allele was always identically rearranged (Fig. 4)Citation , indicating a clonal origin of the tumor. The presence of a few distinct hybridization bands is indicative of the expansion of a small number of particular clones to give rise to a tumor in the animal (as opposed to a smeared signal attributable to different rearrangements from many individual cells). This unique VHDJH rearrangement was confirmed by PCR and sequencing of some tumors, which showed that the rearranged VH genes were not hypermutated, and supports an early origin of the malignant cells (data not shown).



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  		Fig. 4. Southern blot analysis to establish configuration and lineage specificity of the abnormal B-cell population in IgH/c-myc YAC (3, 5, and 11 weeks of age) and E{Delta}IgH/c-myc YAC chimeric mice (20 weeks of age). A JH probe was used to establish the configuration of the mouse IgH locus after EcoRI digest to verify B-cell clonality in mice of different ages, in control spleen (Con), and chimeric spleens (S), and in tumors (T) and spleens derived from the same mouse. G, germ-line band.

 
c-myc Activation.
To gain information about oncogene activation in tumor development, we compared c-myc mRNA levels in different tissues from E{Delta}IgH/c-myc YAC and IgH/c-myc YAC mice of different ages (Fig. 5)Citation . The results show that human c-myc is expressed only in the B-cell compartment (e.g., spleen; Fig. 5ACitation ) and that the high degree of chimerism found in other organs (Fig. 5C)Citation does not result in c-myc activation. Most importantly, however, it appears that although c-myc expression is B cell specific, it is only activated in those B cells responsible for tumor development and not in highly chimeric pretumor spleens (Fig. 5A)Citation . Lipopolysaccharide treatment of spleen cells from chimeric IgH/c-myc mice, where a large number of abnormal cells were present, induced cellular proliferation, but this was not accompanied by an increase in the relative level of c-myc expressed compared with untreated cells. Similarly, in chimeric spleens from very young mice, lipopolysaccharide caused proliferation but did not lead to an increase in c-myc expression (data not shown). In >8-week-old translocus mice, tumor expansion can lead to infiltration of other tissues, such as the thymus (Fig. 3)Citation , which then show a human c-myc band in Northern blot. Interestingly, there was no difference in lymphocyte-specific c-myc activation of the transgene in chimeric mice with or without enhancer, which implies that a not-yet-identified enhancer or LCR type element in the IgH locus core region is responsible for B-cell-dependent oncogene activation and tumor development.



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  		Fig. 5. A, Northern blot analysis to assess human c-myc expression in different E{Delta}IgH/c-myc YAC (E{Delta}) and IgH/c-myc YAC tissues. Samples are: spleen and tumor from a 20-week-old E{Delta}IgH/c-myc mouse and spleen from a 4-week-old E{Delta}IgH/c-myc mouse; IgH/c-myc ES cells (ES), tumor, spleen, thymus, and kidney from a 7-week-old IgH/c-myc mouse; and human Burkitt’s Lymphoma cells (Raji) or normal ES cells (ES Con) as control. Hybridization with a human c-myc probe (Hu myc) shows that expression is B-cell specific. B, Actin (E{Delta}IgH/c-myc) and GAPDH (glyceraldehyde-3-phosphate dehydrogenase; IgH/c-myc) was used to confirm that equivalent amounts of RNA were analyzed. Raji cells were used as control. C, PCR analysis confirming that different tissues from E{Delta}IgH/c-myc YAC and IgH/c-myc YAC mice are highly chimeric. The mouse actin gene and the C{delta} transgene were amplified in parallel with normal ES cells (ES Con) as control.

 
A Mouse Model for B-Cell ALL.
The pathology observed in the IgH/c-myc YAC mice resembles that of mature B-cell ALL, which is equivalent to Burkitt’s lymphoma in leukemic phase (25) , and represents about 5% of ALL (26, 27, 28) . As with the tumors that develop in our YAC-based mice, B-cell ALL is characterized by the presence of large sIg+ cells carrying a c-myc translocation, usually into the IgH locus, which can infiltrate the bone marrow at an early age and lead to abdominal tumors. The profile of tumor development seen in the IgH/c-myc YAC mice is in contrast to that seen in transgenic mice carrying a c-myc/Eµ enhancer minigene construct, where diffuse lymph node enlargement was first noted in mice 2 months of age (5 , 6 , 9) . The activation of tumor development in mice, where the oncogene is adjacent to suspected regulatory elements, must therefore follow a different course to that in the E{Delta}IgH/c-myc YAC-based mice, where tumor development is independent of Eµ. The lack of a distinct role for Eµ in our model parallels the observation that many translocation events do not result in an enhancer element being in the proximity of the oncogene (8 , 10, 11, 12) . Our results indicate that the activation of oncogenes is provided by an as yet unidentified B-cell specific regulatory element(s) located in the core region of the IgH locus, between VH2-5 and ~20 kb downstream of C{delta}.


   ACKNOWLEDGMENTS
 
We are grateful to Drs. M. Neuberger and C. Rada for constructive discussions, to N. Miller for helping with the flow cytometry, D. Melton for the kind gift of HM-1 ES cells, B. Goyenechea for help with the proliferation analysis, and J. Xian for expert technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by a Medical Research Council project grant and by the Babraham Institute through a Biotechnology and Biological Sciences Research Council competitive strategic grant. C.P. is supported by a Beca de Ampliacion de Estudios fellowship from Fondo de Investigaciones Sanitarias (98/5019) and Instituto de Salud Carlos III, Spain, and I. C. N. holds a Howard Florey Fellowship from the Royal Society. Back

2 To whom requests for reprints should be addressed, at Laboratory of Developmental Immunology, Department of Development and Genetics, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom. Phone: 44-1223-496304; Fax: 44-1223-496030; E-mail: Marianne.Bruggemann{at}bbsrc.ac.uk Back

3 The abbreviations used are: IgH, immunoglobulin heavy chain; ALL, acute lymphoblastic leukemia; Eµ, heavy chain intron enhancer; ES, embryonic stem; H, heavy chain; L, light chain; YAC, yeast artificial chromosome. Back

Received 3/29/99. Accepted 9/ 3/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

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