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PubMed1997

TEL is one of the targets for deletion on 12p in many cases of childhood B-lineage acute lymphoblastic leukemia.

Abnormalities of the short arm of chromosome 12 including loss of heterozygosity (LOH) and TEL/AML-1 fusion resulting from a t(12;21)(p13;q22) translocation are frequently observed in childhood acute lymphoblastic leukemia (ALL). We investigated 21 DNA samples of childhood ALL which had LOH at 12p13. Rearrangement of TEL was observed in eight cases and another case showed a homozygous deletion of TEL. Two informative samples with TEL rearrangement had a deletion localized to the 5' region of this gene. The deletion in these two cases includes the helix-loop-helix (HLH) domain. This is consistent with the hypothesis that the normal tel can heterodimerize with the TEL/AML-1 gene product and inhibit the transforming capacity of the chimeric protein. Presumably, loss of the HLH of the normal remaining TEL allele abrogates this tumor suppressor-like function. The case with homozygous deletion of TEL is also consistent with this gene having qualities of a tumor suppressor. One unusual case had T-ALL rather than B-lineage ALL and the leukemic cells had rearrangement of TEL, but they did not have an alteration of the remaining TEL allele suggesting that the etiology of this disease may be different. This analysis further emphasizes the importance of loss of the normal TEL allele in childhood precursor B-lineage ALL.

Blotting, Southern↗
PubMed1997

Unbalanced t(3;12) in a case of juvenile myelomonocytic leukemia (JMML) results in partial trisomy of 3q as defined by FISH.

Juvenile myelomonocytic leukemia (JMML) is a rare disorder of early childhood, to which no recurrent chromosome rearrangement has been yet associated. We report a case where leukemic cells harbored a 46,XX,der(12)t(3;12) (q21 approximately 22;p13.33) karyotype, resulting in partial trisomy of 3q. The origin of chromosome material translocated to chromosome 12 was assessed by chromosome painting using a whole chromosome 3-specific probe. The breakpoint regions were defined by FISH using YAC probes from 3q and 12p chromosomal regions. Interestingly, partial trisomy of 3q has been detected in a previously reported JMML case, consequent to the presence of a der(15)t(3;15)(q13.1;q26). The involvement of a similar chromosome 3 rearrangement in these two JMML cases suggests the hypothesis that either the resulting duplication of some gene/s on 3q or the loss of heterozygosity (LOH) of some gene/s on 3p may be involved in one of the steps leading to JMML. On the other hand, it cannot be ruled out that the relevant mutation in our case might be consequent to the particular breakpoints at bands 3q21 approximately 22 and 12p13.3, that may alter the structure and/or expression of the involved gene/s.

Chromosome Aberrations↗
PubMed1999

The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice.

Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that displays both myelodysplastic and myeloproliferative features. The t(5;12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation fuses the amino terminal portion of the ets family member, Tel, with the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor beta (PDGFRbeta) gene. To investigate the role of this fusion protein in the pathogenesis of CMML, we expressed the Tel-PDGFRbeta fusion cDNA in hematopoietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring express the transgene specifically in hematopoietic tissues and develop a myeloproliferative syndrome characterized by: overproduction of mature neutrophils and megakaryocytes in the bone marrow; splenomegaly with effacement of splenic architecture by extramedullary hematopoiesis; an abnormal population of leukocytes co-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the transgene exhibited at least one of these features of dysregulated myelopoiesis, and 20% progressed to a myeloid or lymphoid malignancy. This murine model of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFRbeta fusion protein in its pathogenesis.

Animals↗
PubMed2001

The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells.

The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.

Animals↗
PubMed2002

The tumor suppressor activity of SOCS-1.

SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 deficient mice die within the first three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 -/- fibroblasts are more sensitive than wild type fibroblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.

Animals↗
PubMed2002

Transformation of Ba/F3 cells and Rat-1 cells by ETV6/ARG.

ETV6/ARG, a novel fusion gene composed of the ETV6 HLH oligomerization domain and most of sequences of the ARG protein tyrosine, was recently identified in human leukemia cells. The presence of the ETV6/ARG translocation raises the possibility that the resulting fusion protein functions as an oncogene. However, the transforming activity of the ETV6/ARG protein has not been determined and its contribution to leukemogenesis is therefore unknown. Here we address this question by analysing the oncogenic activity of ETV6/ARG in hematopoietic and fibroblast cells. It is demonstrated that expression of ETV6/ARG confers IL3-independent growth to Ba/F3 cells and anchorage independent growth to Rat-1 fibroblasts. It is also shown that multiple signaling molecules, including PI3K, SHC, ras-GAP and CRK-L, are tyrosine phosphorylated in Ba/F3 cells that express ETV6/ARG. Analysis of four different types of ETV6/ARG transcripts previously identified in the AML-M3 leukemia cell line HT93A suggest that ETV6 HLH domain is required for oncogenic activity. Based upon these results it is concluded that ARG can be activated as an oncogene in human malignancy and that the ETV6/ARG oncoprotein triggers some of the same signaling pathways associated with activated ABL oncogenes.

Animals↗
PubMed2006

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation.

Tel-Abl and Tel-Jak2 are fusion proteins associated with human haematologic neoplasms. They possess constitutive tyrosine kinase activity and activate common downstream signalling pathways like Stat-5, PI3-K/Akt, Ras/MapK and NF-kappaB. In this study, we showed the specific requirement of Src family members for the Tel-Abl-mediated cell growth, activation of Stat5, PI3-K/Akt and Ras/MapK while dispensable for Tel-Jak2. Hck was found strongly phosphorylated in Tel-Abl-expressing Ba/F3 cells and sensitive to imatinib mesylate treatment, providing evidence that Hck is a target of Tel-Abl tyrosine kinase activity. Overexpression of a kinase dead form of Hck inhibits the proliferation of Ba/F3 cells expressing Tel-Abl as the phosphorylation of Akt and Erk1/2. These results argue for an important role of Hck in Tel-Abl oncogenic signalling.

Benzamides↗
PubMed2000

Recurrent molecular deletion of the 12p13 region, centromeric to ETV6/TEL, in T-cell prolymphocytic leukemia.

INTRODUCTION: T-cell prolymphocytic leukemia is a rare form of mature leukemia which occurs in adults and in younger patients suffering ataxia telangiectasia. Among others, complex chromosome aberrations of chromosome 12 have been described in this disease. We searched for deletions of the 12p13 region as the result of these chromosome rearrangements. MATERIAL AND METHODS: Paired leukemic and non-leukemic cells were obtained from a series of 21 patients suffering T-cell prolymphocytic leukemia. Loss of heterozygosity was searched for by microsatellite typing using a fluorescent automated laser DNA sequencer to analyze the amplification products. Proteins were analyzed by Western blot. Southern blot analysis of one patient was conducted. RESULTS AND CONCLUSION: Loss of heterozygosity of the 12p13 region, including the ETV6 and CDKN1B genes, was detected in nine of these 21 cases (43%). Western and Southern blot analyses of one case demonstrated a biallelic deletion which did not include ETV6. Taken together, our results defined a minimal region of deletion of less than one Mb flanked by the markers b312C2T7 and D12S320, excluding ETV6 as a candidate gene. Deletion of the 12p13 region is thus a highly recurrent genetic event in T-cell prolymphocytic leukemia.

Centromere↗
PubMed2003

Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate.

Most chronic myeloid leukaemia (CML) patients are genetically characterized by the t(9;22)(q34;q11), generating the BCR/ABL1 fusion gene. However, a few CML patients with rearrangements of 9q34 and 12p13, leading to ETV6/ABL1 chimaeras, have also been reported. Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC). A chronic phase was achieved after acute myeloid leukaemia induction therapy. Then, treatment with imatinib mesylate (600 mg/d) was initiated and the effect was assessed clinically as well as genetically, including by repeated interphase fluorescence in situ hybridization studies. Until d 71 of imatinib mesylate therapy, stable improvements in the clinical and laboratory features were noted, and the frequency of ABL1-rearranged peripheral blood cells decreased from 56% to 11%. At d 92, an additional t(12;13)(p12;q13), with the 12p breakpoint proximal to ETV6, was found. The patient relapsed into BC 126 d after the start of the imatinib mesylate treatment and succumbed to the disease shortly afterwards. No mutations in the tyrosine kinase domain of ABL1 of the ETV6/ABL1 fusion were identified in the second BC. However, whereas the ETV6/ABL1 expression was seemingly the same at diagnosis and at second BC, the expression of ETV6 was markedly lower at the second BC. This decreased expression of wild-type ETV6 may have been a contributory factor for the relapse.

Adult↗
PubMed2001

TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3'-kinase/protein kinase B signaling pathway.

A subset of chromosomal translocations that participate in leukemia involve activated tyrosine kinases. The ets transcription factor, TEL, undergoes translocations with several distinct tyrosine kinases including JAK2. TEL-JAK2 transforms cell lines to factor independence, and constitutive tyrosine kinase activity results in the phosphorylation of several substrates including STAT1, STAT3, and STAT5. In this study we have shown that TEL-JAK2 can constitutively activate the phosphatidylinositol 3'-kinase (PI 3'-kinase) signaling pathway. The regulatory subunit of PI 3'-kinase, p85, associates with TEL-JAK2 in immunoprecipitations, and this was shown to be mediated by the amino-terminal SH2 domain of p85 but independent of a putative p85-binding motif within TEL-JAK2. The scaffolding protein Gab2 can also mediate the association of p85. TEL-JAK2 constitutively phosphorylates the downstream substrate protein kinase B/AKT. Importantly, the pharmacologic PI 3'-kinase inhibitor, LY294002, blocked TEL-JAK2 factor-independent growth and phosphorylation of protein kinase B. However, LY294002 did not alter STAT5 tyrosine phosphorylation, indicating that STAT5 and protein kinase B activation mediated by TEL-JAK2 are independent signaling pathways. Therefore, activation of the PI 3'-kinase signaling pathway is an important event mediated by TEL-JAK2 chromosomal translocations.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL.

The TEL gene, which is frequently rearranged in human leukemias of both myeloid and lymphoid origin, encodes a member of the Ets family of transcription factors. The TEL gene is widely expressed throughout embryonic development and in the adult. To determine the requirement for the TEL gene product in development we generated TEL knockout mice (TEL-/-) by gene targeting in embryonic stem cells. TEL-/- mice are embryonic lethal and die between E10.5-11.5 with defective yolk sac angiogenesis and intra-embryonic apoptosis of mesenchymal and neural cells. Two-thirds of TEL-deficient yolk sacs at E9.5 lack vitelline vessels, yet possess capillaries, indicative of normal vasculogenesis. Vitelline vessels regress by E10.5 in the remaining TEL-/- yolk sacs. Hematopoiesis at the yolk sac stage, however, appears unaffected in TEL-/- embryos. Our findings demonstrate that TEL is required for maintenance of the developing vascular network in the yolk sac and for survival of selected cell types within the embryo proper.

Animals↗
PubMed2005

TEL/ETV6 accelerates erythroid differentiation and inhibits megakaryocytic maturation in a human leukemia cell line UT-7/GM.

TEL/ETV6 accelerates erythroid differentiation in the murine erythroleukemia cell line. To clarify the effects of TEL on megakaryocytic maturation as well as erythroid differentiation, we chose the human leukemia cell line UT-7/GM that differentiates into the erythroid and megakaryocytic lineages by treatment with erythropoietin and thrombopoietin, respectively. Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis and accumulation of the erythroid differentiation-specific transcripts such as gamma-globin, delta-aminolevulinic acid synthase-erythroid, and erythropoietin receptor. Moreover, the glycophorin A(+)/glycoprotein IIb(-) fraction appeared more rapidly in the TEL-overexpressing cells. Interestingly, overexpression of TEL was associated with lower levels of the megakaryocytic maturation-specific glycoprotein IIb and platelet factor 4 transcripts under the treatment with thrombopoietin. Consistently, the glycophorin A(-)/glycoprotein IIb(+) fraction increased more slowly in the TEL-overexpressing cells. Finally, expression of endogenous TEL proteins in UT-7/GM cells was down-regulated following erythropoietin and thrombopoietin exposure. All these data suggest that TEL may decide the fate of human erythrocyte/megakaryocyte common progenitors to differentiate towards the erythroid lineage and against the megakaryocytic lineage.

Cell Differentiation↗
PubMed2005

Prospective gene expression analysis accurately subtypes acute leukaemia in children and establishes a commonality between hyperdiploidy and t(12;21) in acute lymphoblastic leukaemia.

We have prospectively analysed and correlated the gene expression profiles of children presenting with acute leukaemia to the Royal London and Great Ormond Street Hospitals with morphological diagnosis, immunophenotype and karyotype. Total RNA extracted from freshly sorted blast cells was obtained from 84 lymphoblastic [acute lymphoblastic leukaemia (ALL)], 20 myeloid [acute myeloid leukaemia (AML)] and three unclassified acute leukaemias and hybridised to the high density Affymetrix U133A oligonucleotide array. Analysis of variance and significance analysis of microarrays was used to identify discriminatory genes. A novel 50-gene set accurately identified all patients with ALL and AML and predicted for a diagnosis of AML in three patients with unclassified acute leukaemia. A unique gene set was derived for each of eight subtypes of acute leukaemia within our data set. A common profile for children with ALL with an ETV6-RUNX1 fusion, amplification or deletion of ETV6, amplification of RUNX1 or hyperdiploidy with an additional chromosome 21 was identified. This suggests that these rearrangements share a commonality in biological pathways that maintains the leukaemic state. The gene TERF2 was most highly expressed in this group of patients. Our analyses demonstrate that not only is microarray analysis the single most effective tool for the diagnosis of acute leukaemias of childhood but it has the ability to identify unique biological pathways. To further evaluate its prognostic value it needs to be incorporated into the routine diagnostic analysis for large-scale clinical trials in childhood acute leukaemias.

Acute Disease↗
PubMed2006

High incidence of the ETV6/RUNX1 fusion gene in paediatric precursor B-cell acute lymphoblastic leukaemias with trisomy 21 as the sole cytogenetic change: a Nordic series of cases diagnosed 1989-2005.

Trisomy 21 is common in ETV6/RUNX1-positive acute lymphoblastic leukaemia (ALL); both these aberrations are associated with a favourable outcome. The prognostic impact of +21 as a sole cytogenetic change could be due to a cryptic t(12;21)(p13;q22). The occurrence of ETV6/RUNX1 was determined in 66 childhood ALLs with an acquired +21 and a chromosome number <51. ETV6/RUNX1 was found in 45% of cases and in the majority (10/18; 56%) of ALLs with sole +21. Event-free survival did not differ between the t(12;21)-positive and -negative cases. Thus, the prognostic impact of +21 is not attributable to cryptic ETV6/RUNX1.

Adolescent↗
PubMed2000

TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1.

TEL is a member of the ETS family of transcription factors that interacts with the mSin3 and SMRT corepressors to regulate transcription. TEL is biallelically disrupted in acute leukemia, and loss of heterozygosity at the TEL locus has been observed in various cancers. Here we show that expression of TEL in Ras-transformed NIH 3T3 cells inhibits cell growth in soft agar and in normal cultures. Unexpectedly, cells expressing both Ras and TEL grew as aggregates. To begin to explain the morphology of Ras-plus TEL-expressing cells, we demonstrated that the endogenous matrix metalloproteinase stromelysin-1 was repressed by TEL. TEL bound sequences in the stromelysin-1 promoter and repressed the promoter in transient-expression assays, suggesting that it is a direct target for TEL-mediated regulation. Mutants of TEL that removed a binding site for the mSin3A corepressor but retained the ETS domain failed to repress stromelysin-1. When BB-94, a matrix metalloproteinase inhibitor, was added to the culture medium of Ras-expressing cells, it caused a cell aggregation phenotype similar to that caused by TEL expression. In addition, TEL inhibited the invasiveness of Ras-transformed cells in vitro and in vivo. Our results suggest that TEL acts as a tumor suppressor, in part, by transcriptional repression of stromelysin-1.

3T3 Cells↗
PubMed2004

TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia.

PURPOSE: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features. EXPERIMENTAL DESIGN: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion. RESULTS: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement. CONCLUSIONS: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.

Artificial Gene Fusion↗
PubMed1998

Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.

Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.

Amino Acid Sequence↗