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Departments of Genetics and Tumor Cell Biology,1 Biochemistry,2 Animal Resource Center, St. Jude Children's Research Hospital, Memphis, Tennessee,4 Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey3
Received 22 September 2004/ Returned for modification 24 November 2004/ Accepted 13 December 2004
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ABSTRACT |
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INTRODUCTION |
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ETS (for E26 transformation specific) transcription factors play important roles in hematopoietic development as well as in oncogenesis (10, 27). For example, TEL1 (for translocation ETS leukemia, also known as ETV6) is required for normal yolk sac angiogenesis and adult bone marrow hematopoiesis (46, 47) and is a frequent target of aberrations involving the short arm of chromosome 12 in various hematopoietic malignancies (13), as well as in some solid tumors (44).
Recently we identified a close homologue of TEL1 coined TEL2, located on the short arm of chromosome 6p21, a position implicated in a variety of cancers (25). TEL2 has highest identity to TEL1 in the pointed (PNT) protein-protein interaction domain (62.5%) and the ETS DNA binding domain (85.4%) (30). TEL2 and TEL1 are most divergent in their central regions, which in TEL1 directs transcriptional repression by binding to corepressors and HDAC3 (7, 22) and in TEL2 contains a putative PEST sequence (residues 138 to 155) (15) that might direct its rapid turnover. Furthermore, unlike TEL1, which is ubiquitously expressed, TEL2 expression is generally restricted to hematopoietic tissues (30).
As monomers, TEL2 and TEL1 can compete for the same recognition element and function as transcriptional repressors (19, 29), but they can also form heterodimers via their PNT domains (30). However, TEL2 and TEL1 play quite different biological roles. For example, while TEL1 inhibits Ras-induced colony formation (45), TEL2 augments it (19). Furthermore, TEL2 but not TEL1 is down-regulated during monocytic differentiation, and enforced TEL2 expression can block this differentiation program (19). Finally, TEL2 is expressed in many human tumor cell lines (www.ncbi.nlm.nih.gov/CGAP) and appears overexpressed in some human leukemia samples (19).
A tumor suppressor role for TEL1 is suggested by its loss during disease progression of TEL-RUNX1-expressing childhood pre-B-cell acute lymphocytic leukemia (B-ALL) (13, 33, 34). TEL-2's biological effects, and its ability to form heterodimers with TEL1, suggest that TEL2 may antagonize TEL1 functions and thus act as an oncogene. Here we report that TEL2 indeed is an oncogene that cooperates with Myc in lymphoma development and that TEL2 and MYC expression levels are coordinately elevated in a subset of pediatric B-ALL patients. Therefore, TEL2 and MYC also appear to cooperate to promote human B-cell lymphomagenesis.
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MATERIALS AND METHODS |
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For secondary transplants, BMCs of diseased BMTMYCTEL2 mice were collected as described above, and 106 cells were transplanted into sublethally irradiated (450 cGy) C57BL/6/129svJ mixed-background mice.
GFP expression in peripheral blood of transplanted mice. BMTMycTEL2 and BMTMycvector mice were bled monthly by orbital sinus puncture until the time of euthanasia (2.5 to 4 months posttransplantation). Blood (20 µl) was collected in 1 ml of phosphate-buffered saline for FACS analysis of erythrocytes and platelets. After lysis of erythrocytes in Gey's solution, the percentage of GFP+ leukocytes was determined. Dead cells were omitted from the analysis after staining with propidium iodide (PI; 0.018 mg/ml) and electronic gating to select PI-negative cells. The number of GFP+ lymphocytes in the peripheral blood was determined by measuring the percentage of GFP+ cells in the area of forward and sideward scatter of the FACS plot coinciding with that of lymphocytes, multiplied by the total number of white blood cells as determined by differential counts using a Hemavet 3700 (Drew Scientific, Cumbria, United Kingdom).
Mouse tissue collection. All animal procedures were carried out in accordance with the U.S. Public Health Service policy on the humane care and use of laboratory animals. Both BMTMycTEL2 and BMTMycvector mice were euthanized 3 to 4 months after transplantation. For protein analyses, tissues were collected and snap-frozen in liquid nitrogen. For staining purposes, tissues were fixed in 10% paraformaldehyde overnight, prior to paraffin embedding, sequential sectioning, and histological staining.
Retroviruses.
The retroviral vectors MSCV-TEL2-IRES-GFP, MSCV-TEL2DBDM-IRES-GFP, and MSCV-TEL2
PNT-IRES-GFP have been described elsewhere (19).
FACS analyses. To determine the lineage of cells in the bone marrow of diseased BMTMycTEL2 mice, the first few moribund animals were assessed for the following lineage markers: Mac1, Gr1, Thy 1.2, CD3, CD4, CD8, B220, immunoglobulin M (IgM), Sca1, c-Kit, and CD34. Because the mice clearly died of a B-lymphoid disease (B220+, partly IgM+), all subsequent animals were only checked for the lymphoid markers B220 and IgM. Single-cell suspensions of bone marrow were made in staining medium (SM; Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 20 mM sodium azide) containing 100 mg of gamma globulin (Sigma)/ml to block Fc receptors. After incubating for 30 min on ice, cells were washed and suspended in SM containing a titered excess of monoclonal antibodies (anti-sIgM [Southern Biotechnology Associates, Birmingham, Ala.] and anti-B220 [Pharmingen]) for 30 min on ice. Cells were then washed and resuspended in SM containing PI (0.018 mg/ml), filtered through 40-µm nylon mesh (Small Parts, Inc., Miami, Fla.), and analyzed using a BD Biosciences FACSCalibur flow cytometer. Dead cells were excluded from the analysis by electronic gating to select PI-negative cells.
Protein analyses. Protein extracts were prepared from mouse tissues, wild-type pro-B cells, or pro-B cells transduced with TEL2 retrovirus, using TRIzol reagent (Invitrogen, Carlsbad, Calif.) according to the manufacturer's instructions. The proteins were quantified using the bicinchoninic acid protein assay reagent (Pierce Chemical Co., Rockford, Ill.). Proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (10% gel) under reducing conditions and transferred to a polyvinylidine difluoride membrane (Millipore, Billerica, Mass.). Membranes were incubated with antibodies specific for p53 (Ab-7; Calbiochem, La Jolla, Calif.); p19 ARF (ab80; Abcam, Cambridge, United Kingdom); anti-actin (I-19 sc-1616; Santa Cruz); Bcl2 (554218; BD PharMingen); E2f1 (32-1400; Zymed Laboratories Inc., San Francisco, Calif.); c-Myc, ß-catenin, and Mdm2 (Santa Cruz); and Bcl-XL (Transduction Laboratories, Lexington, Ky.). The blots were developed by using the enhanced chemiluminescence kit (NEN-Perkin Elmer Life Sciences, Torrance, Calif.).
TEL2 antibody production. Because our original TEL2 antibody (30) had a low affinity, we raised a new antibody. A peptide corresponding to the 14 carboxy-terminal amino acids (DRIEFKDKRPEISP) of TEL2 was synthesized, conjugated to keyhole limpet hemocyanin, and injected into New Zealand White rabbits (Rockland, Gilbertsville, Pa.). TEL2-specific antibodies were affinity purified on a CH-activated Sepharose 4B column (Sigma) with coupled DRIEFKDKRPEISP peptide.
In vitro culture of pro-B cells and retroviral infections.
The BMCs of 4- to 6-week-old C57BL/6/129svJ mixed-background mice were harvested from the femurs and tibiae. After hypotonic lysis of the red blood cells in Gey's solution, the cells were plated on an S17 stromal layer (35) in RPMI 1640 medium supplemented with 10% fetal calf serum (HyClone), 55 µM 2-mercaptoethanol, 2 mM glutamine, penicillin (100 IU/ml), streptomycin (100 µg/ml), and murine IL-7 (50 ng/ml) to stimulate the outgrowth of B-cell progenitors. After 1 week of culture, the surviving cells were immunophenotyped by flow cytometry, and over 95% of cells were positive for the markers B220+ and CD43+ but negative for IgM, T-cell-specific or myeloid/macrophage-specific markers, consistent with a pro-B-cell phenotype (data not shown). The pro-B cells were infected twice daily for 48 h with retroviral vectors MSCV-IRES-GFP, MSCV-TEL2-IRES-GFP, MSCV-TEL2DBDM-IRES-GFP, and MSCV-TEL2PNT-IRES-GFP in the presence of Polybrene (8 µg/ml) and IL-7. Infected GFP+ cells were sorted by FACS and expanded in liquid culture in IL-7-containing growth medium. Greater than 98% of cells in the pro-B-cell-TEL2 cultures were GFP+.
Cell cycle analysis and Annexin-V staining of cultured pro-B cells. Wild-type and TEL2-expressing pro-B cells were cultured on S17 stromal cells with IL-7. Apoptotic cells were identified by FACS after Annexin-V-fluorescein isothiocyanate staining, and PI staining was used to exclude dead cells. Cell cycle analysis was performed by FACS by quantitative staining of the DNA in cell nuclei through a rapid one-step protocol with PI. Briefly, the samples were prepared at a concentration of 106 cells/ml and washed in a hypotonic solution containing PI and 0.1% Triton X-100, resulting in bare nuclei that are quantitatively stained with PI. The nuclei were treated with DNase-free RNase and filtered through a 40-µm-diameter mesh to eliminate clumps of nuclei. Finally, the percentages of cells within G0/G1, S, or G2/M were determined by measuring the DNA content using flow cytometry.
Patient samples and real-time quantitative RT-PCR. With the approval of the St. Jude Children's Research Hospital Institutional Review Board, patient samples were obtained from Istanbul University, Institute for Experimental Medicine, Department of Genetics. Bone marrow samples were collected at the time of diagnosis from children with ALL or from healthy donors, with informed consent of their parents according to Turkish law. No identifiers were linked to any of these patient samples. Mononuclear cells were separated by Ficoll-Hypaque centrifugation. Total RNA was isolated by guanidium thiocyanate-phenol-chloroform extraction, and cDNA synthesis was performed using 1 µg of RNA and random hexamer primers. Real-time reverse transcription-PCR (RT-PCR) was performed using a 7900HT sequence detection system (ABI, Foster City, Calif.), TaqMan universal PCR master mix reagents, and a 1/10 volume of the cDNA. Human TEL2 and MYC primers and probes were designed using Primer Express version 2.0 software (ABI). Amplification of 18S rRNA was performed in the same reaction tube as an internal control with an alternatively labeled probe (ABI). cDNA from total RNA of normal bone marrow (bone marrow pooled from eight male and eight female Caucasians; BD Bioscience) and four separate healthy donors was analyzed, and the average value of these samples was used as a control. Triplicate experiments were performed for each of the control and experimental samples.
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RESULTS |
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Following 5-fluorouracil treatment, bone marrow cells from preneoplastic Eµ-Myc mice were infected with MSCV-TEL2-IRES-GFP or control MSCV-IRES-GFP retroviruses (Fig. 1A) and then transplanted into 18 lethally irradiated syngeneic mice in three independent experiments. The course of disease was monitored by eye bleeds of mice transplanted with an equal number of BMCs that were transduced at equal efficiency (
50% GFP+) (Fig. 1B). The average number of GFP+ lymphocytes in the peripheral blood of mice transplanted with Eµ-Myc bone marrow expressing TEL2 (BMTMycTEL2) was slightly augmented at 1 month (1.5 x 103/µl) versus those receiving vector alone (BMTMycvector; 103/µl) (Fig. 1B). In the following 2 months, the numbers of GFP+ lymphocytes in peripheral blood decreased slightly in BMTMycvector mice to 0.8 x 103/µl. Strikingly, the numbers of GFP+ lymphocytes in the peripheral blood of BMTMycTEL2 mice almost doubled by the second month (2.1 x 103/µl) and increased an additional 15-fold (35.1 x 103/µl) by the third month. Therefore, TEL2 provides a profound growth advantage to Myc-expressing B lymphocytes.
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To confirm that TEL2 transcriptional activity was required for cooperation with Myc, we also evaluated the activity of a TEL2-DNA-binding domain mutant (DBDM) that fails to bind DNA (19). Bone marrow derived from precancerous Eµ-Myc mice was infected with MSCV-TEL2-DBDM-IRES-GFP or MSCV-TEL2-IRES-GFP retroviruses, and these cells expressed comparable levels of TEL2-DBDM and TEL2 proteins (data not shown). Lethally irradiated mice were then transplanted and observed for disease. All BMTMycTEL2 mice developed lympholeukemia within 4 months, whereas the BMTMycTEL2-DBDM mice, like BMTMycvector recipients, lacked signs of disease until 6 to 7 months posttransplant. Therefore, TEL2 must bind to its target genes to cooperate with Myc in lymphomagenesis.
p53 is mutated in Eµ-Myc/TEL2 tumors.
Genes that cooperate with Myc in the Eµ-Myc lymphoma model often disable Myc's apoptotic response (11, 12, 38-40). The emergence of lymphoma in Eµ-Myc transgenic mice is associated with inactivation of the p53 tumor suppressor pathway in most tumors (11) through missense point mutations in p53 that create dominant-negative forms of the protein (25% of lymphomas), biallelic deletion of Arf (25%), and/or overexpression of Mdm2 (50%) (11). Immunoblotting using an anti-TEL2 antibody confirmed that all Eµ-Myc/TEL2 tumors expressed high levels of TEL2 protein (Fig. 3A). Strikingly, supraphysiological levels of p53, a hallmark of p53 mutations (11), were evident in 12 out of 15 lymphomas arising in BMTMycTEL2 mice (Fig. 3A, lanes 1 to 15), compared to absent or low levels of p53 expressed in FACS-analyzed B220+ normal spleen cells and in BMTMycvector spleen cells (Fig. 3A, lanes B220, Eµ-Myc T, and BMTMycvector). p53 negatively regulates the transcription of Arf (42), and thus another hallmark of tumors bearing p53 mutations is a dramatic up-regulation of Arf protein levels (11). Indeed, moderate to high levels of p19Arf protein were detected in all but one lymphoma of Eµ-Myc/TEL2 BMT mice (Fig. 3A). Thus, there is a marked bias towards p53 mutations in tumors of Eµ-Myc/TEL2 BMT mice.
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PNT, which lacks the pointed protein-protein interaction domain (19), or TEL2-DBDM were comparable to vector-only-transduced cell cultures in their growth properties (data not shown). To determine the effects of TEL2 on pro-B-cell survival, we performed Annexin-V assays in the presence or absence of S17 stroma and IL-7. Notably, in the presence of S17 stroma and IL-7, TEL2-expressing pro-B cells showed a threefold lower apoptotic index than wild-type or vector-transduced pro-B cells (Fig. 5C). TEL2 also provided a remarkable short-term survival advantage to pro-B cells when they were deprived of IL-7 and S17 stroma contacts (Fig. 5C). Therefore, TEL2's effects on promoting survival may also contribute to the increased proliferative rates of TEL2-expressing B cells.
These findings suggested that TEL2 targets both cell cycle and apoptotic regulators. We therefore canvassed likely culprits in these responses, including the cell cycle regulators E2f1, c-Myc, p27KIP1, and p16ink4a and the apoptotic regulators Bcl-2 and Bcl-XL. By 1 month of culture, there were obvious increases in the levels of E2f1 and c-Myc in TEL2-expressing versus control pro-B-cell cultures (Fig. 5D), but there was essentially no change in the levels of p27KIP1 (data not shown). Further, although there were no differences in Bcl-XL expression (data not shown), there was a marked up-regulation of Bcl-2 levels in TEL2-expressing pro-B cells (Fig. 5D). Myc suppresses Bcl-2 and Bcl-XL expression in B cells, and bypass of this pathway also contributes to Myc-induced lymphomagenesis (12). Therefore, TEL2 may impair Myc-induced apoptosis through its ability to up-regulate Bcl-2. Indeed, immunoblotting confirmed that malignant spleen cells of Eµ-Myc/TEL2 BMT mice expressed high levels of Bcl-2 (Fig. 4B), while precancerous B220+, IgM– Eµ-Myc spleen cells express very low levels of Bcl2 (12).
Strikingly, unlike wild-type- or vector-only-transduced cultures that slowed in their growth rates and senesced by 1 to 2 months, TEL2-expressing pro-B cells grew indefinitely without undergoing replicative crisis. Therefore, TEL2 behaves as an immortalizing oncogene in pro-B cells. Immortalization of mouse cells usually involves missense mutations of p53 or deletion or silencing of Arf or p16Ink4a (18, 32, 48, 49). We therefore assessed the status of p53, Arf, and p16Ink4a of TEL2-expressing pro-B cells with time in culture. Immortalization via p53 mutations provokes profound increases in p53 protein and in p19Arf, due to the loss of the p53-to-Arf feedback loop (18, 32, 48). However, p53 protein levels remained very low in TEL2-expressing cultures. A modest increase in p19Arf protein was noted, but by 4 months Arf expression was entirely silenced (Fig. 5D), consistent with studies showing that loss of Arf alone is sufficient to immortalize mouse pre-B cells in culture (32). Loss of p19Arf protein likely occurred through selective silencing of Arf transcription, as with time TEL2-expressing cultures showed significant increases in p16Ink4a (Fig. 5D), similar to that noted in pre-B-cell lines established from Arf-null mice (32). Therefore, TEL2-induced immortalization involves loss of Arf but not p16Ink4a.
TEL2, MYC, and MYCN are overexpressed in a subset of human B-ALL. TEL2 is not present in the mouse genome, but because TEL2 cooperated with Myc in lymphoma development in Eµ-Myc transgenic mice, we evaluated TEL2 expression in human BL, which bears MYC/Ig translocations (3, 16). However, quantitative RT-PCR of 14 primary, sporadic BL samples established that TEL2 was overexpressed in only one BL sample relative to its expression in normal peripheral blood CD19+ B lymphocytes (Fig. 6A). Therefore, activation of TEL2 appears infrequent in sporadic BL.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TEL2 is located on chromosome 6p21, a region implicated in a number of cancers, including chondroid hamartomas, thyroid adenomas, ductal carcinoma in situ of the breast, B-cell non-Hodgkin's lymphoma, cervical cancer, astrocytoma, non-small cell lung carcinomas, and ovarian carcinomas (20, 24, 26). Elevated levels of TEL2 have been reported in some cancer cell lines (15) and in various leukemia samples, including B-ALL (19, 29). However, despite these correlative data, there was heretofore no causal link between TEL2 expression and tumor development in humans.
TEL2 is expressed at very low levels in most tissues (29) but is expressed at higher levels in hematopoietic tissues (30). TEL2 promotes Ras-induced transformation and inhibits vitamin D3-induced differentiation of HL60 and U937 myeloid cells (19). In addition, enforced TEL2 expression in mouse bone marrow results in a myeloproliferative disease with a long latency period and its expression in Arf-null bone marrow promotes B-cell lymphomagenesis (C. Carella and G. Grosveld, unpublished results), further supporting the notion that TEL2 functions as an oncogene. Indeed, our results establish that the antiapoptotic and growth-promoting activities of TEL2 cooperate with c-Myc in B lymphomagenesis and that TEL2 impairs Myc-induced apoptosis. One expectation from our TEL2/Eµ-Myc studies was that TEL2 would also show involvement in BL and, indeed, many BL carry missense point mutations in P53 or other defects in the p14ARF-HDM2-p53 pathway (36). However, connections between TEL2 and MYC in BL were rare. Nonetheless, there is simultaneous up-regulation of TEL2 and MYC/MYCN in pediatric patients with B-lymphoid malignancies, and we postulate this combination contributes to lymphomagenesis in these cases. There was no correlation of elevated TEL2 expression with disease prognosis, survival rate, FAB subtype, or white cell counts.
TEL2 promotes B-cell survival. The data presented herein suggest that TEL2 transcription functions cooperate with Myc, at least in part, through its ability to inhibit Myc-induced apoptosis. However, the emergence of tumorigenic clones in Eµ-Myc/TEL2 mice only occurred when Myc's apoptotic pathways were disabled through p53 mutations. We therefore propose that TEL2's effects on enhancing B-cell proliferation contribute to accelerated disease by enlarging the cycling B-cell compartment in Eµ-Myc mice, thereby increasing chances for p53 mutations. Similar effects can also be accomplished by overexpressing antiapoptotic proteins, such as Bcl2 or Bcl-XL (6, 43), and it is thus also notable that a hallmark of Eµ-Myc/TEL2 lymphomas was a marked up-regulation in Bcl-2, which is suppressed in precancerous B cells of Eµ-Myc transgenic mice (12). The Bcl-2 promoter harbors several elements that respond to Ets transcription factors (8), but at present it is unclear whether TEL2 directly regulates Bcl-2. However, a widespread role for Ets transcription factors regulating apoptosis has been proposed. For example, Ets2 inhibits apoptosis following growth factor deprivation by inducing Bcl-X (41), whereas TEL1 promotes apoptosis by down-regulating Bcl-X (17). Up-regulation of Bcl-2 by TEL2 is particularly relevant in pre-B cells, where Bcl-2 expression is normally low and Bcl-XL is high (14). Thus, TEL2's ability to augment Bcl-2 expression in this compartment would be predicted to spare pre-B cells at risk of suicide, particularly those that overexpress Myc, and elevated levels of Bcl-2 are also likely responsible for the delayed programmed cell deaths of TEL2-expressing pre-B cells following the withdrawal of IL-7 and stromal contacts (Fig. 5C).
TEL2 accelerates B-cell proliferation. Enforced expression of TEL2 in cultured pre-B cells increases the expression of both c-Myc and E2f1 (Fig. 5D). Since the growth-promoting effects of Myc are dependent upon E2f1 in pre-B cells (5), increases in the thresholds of these two transcription factors likely mediate TEL2's ability to augment pre-B-cell proliferation. This fits well with the simultaneous up-regulation of Arf in TEL2-expressing cells, which responds to proliferative signals coming from Myc (11, 48) or E2f1 (4, 9). We favor this over a direct induction of Arf by TEL2, as TEL2 has only been shown to repress transcription. Finally, the combined effects of c-Myc and E2f1 put TEL2-expressing B cells under proliferative stress, a condition under which cells would be predisposed to losing and/or silencing Arf, a scenario operational during TEL2-directed B-cell immortalization.
MYC and TEL2 in human B-cell lymphomas. Although cooperation between MYC and TEL2 appears infrequent in sporadic human BL, approximately one-third of B-ALL samples displayed coordinated elevated expression of MYC/MYCN and TEL2. The frequency of elevated TEL2 expression in this cohort of pediatric patient samples (34.8%) is considerably higher than in a previous cohort of pediatric ALL (8.7%) which was, however, biased towards t(12;21) pre-B-ALL patients (19). Given our experience with the mouse model, the MYC/TEL2 combination is likely important in human lympholeukemia, and perhaps TEL2 should be considered as a diagnostic and/or therapeutic target in these malignancies.
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ACKNOWLEDGMENTS |
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PNT-IRES-GFP retroviral vectors and Blake McGourty for the supply of C57BL/6/129svJ mixed-background mice and technical assistance. We also thank the Sherr and Roussel labs for providing Arf and p16ink4A antibodies. We gratefully acknowledge Ann-Marie Hamilton Easton and Richard Ashmun for expert FACS analysis, and we thank Charlette Hill for editing the manuscript. This work was supported by NCI grants RO1-CA72999-08 (G.C.G.) and RO1 CA76379-07 (J.L.C.), the Cancer Center (CORE) support grant CA21765, Istanbul University Research Fund project no. 1554/16012001, and by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital.
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FOOTNOTES |
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Supplemental material for this article may be found at http://mcb.asm.org/.
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