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PubMed2006

The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase.

Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.

Animals↗
PubMed2004

TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity.

The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality yet identified in any pediatric leukemia and gives rise to the TEL-AML1 fusion product. To investigate the effects of TEL-AML1 on hematopoiesis, fetal liver hematopoietic progenitor cells (HPCs) were transduced with retroviral vectors expressing this fusion protein. We show that TEL-AML1 dramatically alters differentiation of HPCs in vitro, preferentially promoting B-lymphocyte development, enhancing self-renewal of B-cell precursors, and leading to the establishment of long-term growth factor-dependent pre-B-cell lines. However, it had no effect on myeloid development in vitro. Further experiments were performed to determine whether TEL-AML1 also demonstrates lineage-specific activity in vivo. TEL-AML1-expressing HPCs displayed a competitive advantage in reconstituting both B-cell and myeloid lineages in vivo but had no effect on reconstitution of the T-cell lineage. Despite promoting these alterations in hematopoiesis, TEL-AML1 did not induce leukemia in transplanted mice. Our study provides a unique insight into the role of TEL-AML1 in leukemia predisposition and a potential model to study the mechanism of leukemogenesis associated with this fusion.

Animals↗
PubMed2000

TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia.

The t(12;21) translocation resulting in TEL/AML1 gene fusion is present in approximately 25% of patients with precursor B-lineage pediatric acute lymphoblastic leukemia (ALL). Studies suggest an association with a good prognosis; however, relapse can occur. We studied the relation between t(12;21), determined by fluorescence in situ hybridization or polymerase chain reaction, and in vitro drug resistance, measured by the MTT assay, in childhood B-lineage ALL at diagnosis. A total of 180 ALL samples were tested, 51 (28%) of which were positive for t(12;21). The median LC(50) values did not differ significantly between TEL/AML1-positive and -negative samples for prednisolone, dexamethasone, daunorubicin, thiopurines, epipodophyllotoxins, and 4-HOO-ifosfamide. However, the TEL/AML1-positive patients were relatively more sensitive to L-asparaginase (ASP; 5.9-fold; P =.029) and slightly but significantly more resistant to vincristine (1.5-fold; P =.011) and cytarabine (1.5-fold; P =.014). After matching for unevenly distributed patient characteristics-that is, excluding patients younger than 12 months, patients with CD10-negative immature B-lineage ALL, patients with Philadelphia chromosome, and patients who were hyperdiploid (more than 50 chromosomes) from the TEL/AML1 negative group-the only remaining difference was a relative sensitivity for ASP in the TEL/AML1-positive samples (10.8-fold; P =. 012). In conclusion, the presence of TEL/AML1 gene fusion in childhood precursor B-lineage ALL does not seem to be associated with a high in vitro drug sensitivity, except for ASP, indicating that these patients could benefit from treatment schedules with significant use of this drug.

Antineoplastic Agents↗
PubMed2001

Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13).

Recently, we and others reported a recurrent t(7;12)(q36;p13) found in myeloid malignancies in children < or =18 months of age and associated with a poor prognosis. Fluorescence in situ hybridization studies mapped the 12p13 breakpoint to the first intron of ETV6 and narrowed down the region of 7q36 involved. By using the sequences made public recently by the Human Genome Project, two candidate genes in 7q36 were identified: the homeobox gene HLXB9 and c7orf3, a gene with unknown function. Reverse transcription-PCR of two cases with t(7;12), using primers for c7orf3 and ETV6, was negative. However, reverse transcription-PCR for HLXB9-ETV6 demonstrated alternative splicing; the two major bands corresponded to fusion of exon 1 of HLXB9 to exons 2 and 3, respectively, of ETV6. The reciprocal ETV6-HLXB9 transcript was not detected. It remains to be elucidated if the leukemic phenotype is attributable to the formation of the HLXB9-ETV6 fusion protein, which includes the helix-loop-helix and E26 transformation-specific DNA binding domains of ETV6 or to the disruption of the normal ETV6 protein.

Acute Disease↗
PubMed2001

Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation.

Fusions of the ETV6/TEL gene to receptor or protein tyrosine kinases (TKs), such as PDGFRbeta, JAK2, ABL, ABL2, TRKC, and Syk, have been reported in various hematological malignancies. Expression of the resultant chimeric proteins is believed to lead to constitutive TK activity through activation by the helix-loop-helix (HLH) domain of ETV6. We identified a novel ETV6 partner gene, fibroblast growth factor receptor 3 (FGFR3), in a patient with peripheral T-cell lymphoma (PTCL) with a t(4;12)(p16;p13) translocation. The ETV6-FGFR3 transcript showed a fusion of exon 5 of ETV6 to exon 10 of FGFR3, resulting in an open reading frame for a chimeric protein consisting of the HLH domain of ETV6 and the TK domains of FGFR3. This is the first report of ETV6 and FGFR3 involvement in PTCL.

Amino Acid Sequence↗
PubMed2003

Secretory carcinoma of the breast: a genetically defined carcinoma entity.

Secretory carcinomas (SBC) are characterized by their characteristic histomorphology and more favorable prognosis compared to invasive ductal carcinoma of usual type (IDC). On this basis, 13 SBCs are evaluated by molecular and immunohistochemical (IH) methods. 13 SBCs and 4 IDCs were analyzed for ETV6-NTRK3 gene fusion by reverse transcriptase-polymerase chain reaction (RT-PCR) and by Fluorescence in situ Hybridization (FISH). 8 of 13 microdissected SBCs with evaluable DNA were evaluated for genetic alterations (GA) by comparative genomic hybridization (CGH). IH included estrogen-receptor (ER), progesterone-receptor (PR), Her-2/neu and Ki-67 (MIB-1) in all 13 cases. Molecular and immunohistochemical results in SBCs were compared with previous data regarding immunohistochemical and molecular characteristics of IDCs. 12 of 13 (92 %) SBC cases, but not IDCs expressed the ETV6-NTRK3 fusion gene which encodes a chimeric tyrosine kinase. Retroviral transfer of ETV6-NTRK3 (EN) into murine mammary epithelial cells resulted in transformed cells that readily formed epithelial tumors in nude mice. CGH revealed an average of 2.0 GAs (range 0-6), including recurrent gains of chromosome 8q and 1q and losses of 22q. Four SBCs were positive for ER and 2 were positive for PR. The mean MIB-1-labeling index was 11.4% (range: <1-34%). Her-2/ neu protein overexpression was detected in 1 case (score 3+). Compared to previous findings in IDCs, SBCs are characterized by the recurrent expression of ETV6-NTRK3 fusion gene, a relatively low number of GAs, low proliferative rate, infrequent Her-2/ neu protein overexpression and a lower rate of steroid hormone receptor expression. These results support the hypothesis that SBCs have immunohistochemical and genetic features that specifically distinguish them from IDCs.

3T3 Cells↗
PubMed1996

p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines.

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL which causes chronic myelogenous leukemia. Two different fusion proteins can be produced, p190BCR/ABL and p210BCR/ABL, depending on the location of the breakpoint in BCR. Although the ABL tyrosine kinase activity of the resulting oncoprotein is essential for transformation, the exact functional contribution of BCR to transformation is unclear. A novel oncogene containing ABL is formed by the (9;12) translocation which fuses part of the ets-family member TEL to c-ABL in patients with acute leukemia. In an effort to compare the biological effects of various ABL oncogenes, we transformed two different factor-dependent murine hematopoietic cell lines with cDNA's encoding p210BCR/ABL, p190BCR/ABL, or TEL/ABL. Transfection of each of the three activated ABL oncogenes resulted in rapid emergence of growth factor-independence, and 2-4 sublines from each cell line with each oncogene were further studied. Each oncogene induced an increase in the tyrosine phosphorylation of cellular proteins and autophosphorylation of the oncoprotein itself. Overall, the pattern of increased tyrosine phosphorylation was similar in the cell lines, suggesting that many of the major substrates were identical. We specifically examined a series of proteins known to be p210BCR/ABL substrates, including rasGAP, Shc, SH-PTP2, SH-PTP1, CRK-L, CBL, paxillin, and STATs, and found that each were also tyrosine phosphorylated in response to p190BCR/ABL and TEL/ABL. These results suggest that the function of BCR can be largely replaced by the unrelated protein TEL with regards to transformation of murine hematopoietic cell lines to factor-independence, and support the hypothesis that a major contribution of both fusion partners is to activate the ABL tyrosine kinase.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St Jude Total Therapy Study XII.

To determine the frequency and prognostic significance of recently described genetic lesions in pediatric acute lymphoblastic leukemia (ALL), all cases with available leukemic cell samples treated on St Jude Study XII were analyzed by molecular techniques for alterations of the p16, MLL and ETV6 genes. Homozygous p16 deletion was seen in 36 of 155 cases, including 14 of 23 T cell cases, but had no prognostic value. Rearrangement of MLL was seen in nine of 170 cases (5%) and conferred a poor prognosis, with a 5-year EFS estimate of only 11 +/- 7%, compared with 74 +/- 5% for the germline MLL group (P=0.0001). By contrast, rearrangement of ETV6 was found in 35 cases (21%) and was significantly associated with a better outcome (5-year EFS estimates: 87 +/- 7% vs 64 +/- 6%). In a Cox regression model adjusted for age, DNA index, race, leukocyte count, treatment group, and CNS status, ETV6 rearrangement retained independent prognostic significance (two-sided P value 0.012). Thus, in this uniformly treated group of patients, we confirmed the unfavorable prognostic significance of MLL rearrangement and demonstrated the favorable impact of ETV6 rearrangement, suggesting that these factors be added to ALL risk classification schemes.

Carrier Proteins↗
PubMed2000

Analysis of ETV6/AML1 abnormalities in acute lymphoblastic leukaemia: incidence, alternative spliced forms and minimal residual disease value.

The t(12;21)(p13;q22) translocation, resulting in the fusion of the ETV6 and AML1 genes, occurs in 20-25% of paediatric B-lineage acute lymphoblastic leukaemias (ALL). The identification of the fusion product has important prognostic and therapeutic implications as the translocation has been associated with a favourable clinical outcome. The aim of this study was threefold: (i) to assess the frequency and clinical association of the fusion gene in patients with and without a cytogenetically detectable chromosome 12 and/or 21 abnormality or failed cytogenetic results, (ii) to characterize alternative forms of ETV6/AML1 transcripts, and (iii) to use ETV6/AML1 as a molecular marker for the investigation of minimal residual disease (MRD). ETV6/AML1 fusion was detected in 22 (39%) of 56 cases studied by reverse transcriptase polymerase chain reaction (RT-PCR). ETV6/AML1 fusion was found in nine out of 16 (56%) cases with a cytogenetically visible chromosome 12 abnormality, but also in nine out of 29 patients (31%) without a chromosome 12 abnormality or patients with failed cytogenetics (four out of 11 patients, 36%), making this the most common cytogenetic abnormality in childhood ALL. Alternatively spliced ETV6/AML1 forms were investigated in 14 of the positive patients. Exon 5 of ETV6 was fused in frame to all AML1 exons, except exon 4. Fusion to exon 6 of AML1 resulted in one amino acid change. The presence of ETV6/AML1 was associated with a lower white blood cell count (Student's t-test; P = 0.009) and common (c)ALL phenotype (chi(2) test; P > 0.001), but no better disease-free survival. Our study shows that (i) RT-PCR is the most effective approach for the detection of t(12;21) in childhood ALL, (ii) the association of ETV6/AML1 and chromosome 12 and/or 21, seen in 56% of our cases, further confirms existing data, (iii) overall survival of patients with t(12;21) was not better than other cytogenetics groups, and (d) MRD analysis using ETV6/AML1 fusion is specific, but not sensitive enough to avoid false negative results.

Adolescent↗
PubMed2004

Paucity of TEL-AML 1 translocation, by multiplex RT-PCR, in B-lineage acute lymphoblastic leukemia (ALL) in Indian patients.

A total of 69 patients of B lineage ALL, 35 children (32 males, 3 females) and 34 young adults (27 males, 7 females) were studied by multiplex RT-PCR to determine the relative frequency of t(9;22), t(12;21), t(1;19), and t(4;11,). Translocation (9;22) was seen in 1/35 (2.8%) and t(1;19) in 2/35 (5.7%) children. None of the children showed t(12;21) and t(4;11) translocations. In young adults, t(9;22) and t(1;19) were seen in 5/34 (14.7%) and 2/34 (5.8%) patients, respectively. None of the latter showed t(12;21) or t(4;11) translocations. Thus, there appears to be a significant under representation of the fusion transcripts for TEL-AML, a good prognostic marker, in this study, unlike in the West, where it is seen in 35% of children with ALL. This, together with the generally increased leukemic burden seen in Indian patients, may explain in part, the poor treatment outcome reported.

Adolescent↗
PubMed2004

ETV6/RUNX1 rearrangement in childhood B-precursor acute lymphoblastic leukemia with normal karyotypes or without cytogenetic results.

The ETV6/RUNX1 rearrangement (also known as TEL/AML1) was evaluated in 39 children with B-precursor acute lymphoblastic leukemia (ALL) who had a normal karyotype or lack of mitoses. Forty-one point six percent of patients with normal karyotypes and 66.6% of patients without mitoses presented with the ETV6/RUNX1 rearrangement. In addition to this rearrangement, eight patients showed loss of the normal ETV6 allele; of three patients without mitoses, two showed an extra signal of the RUNX1 gene and the third showed the fusion gene duplicated and loss of the normal ETV6 allele. One patient without the ETV6/RUNX1 rearrangement and without mitoses showed two extra signals of the RUNX1 gene.

Child↗
PubMed1999

Prenatal origin of acute lymphoblastic leukaemia in children.

BACKGROUND: There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally. METHODS: We identified, by reverse-transcriptase PCR screening of blood or bone marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AML1 fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AML1 genomic fusion sequences in neonatal blood spots from each child. FINDINGS: We initially identified TEL-AML1 fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AML1 sequence that suggested prenatal origin in one twin. Three children were excluded because control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative. INTERPRETATION: Our findings showed that childhood acute lymphoblastic leukaemia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also required.

Burkitt Lymphoma↗
PubMed2001

Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study.

TEL/AML1 gene fusion that results from a cryptic t(12;21) is the most common genetic aberration in childhood B-lineage acute lymphoblastic leukemia (ALL). While the translocation may initiate the leukemic process, critical secondary genetic events are currently believed to be pivotal for leukemogenesis. We investigated 12 cases of childhood ALL with TEL/AML1 gene fusion by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) and documented additional or secondary genetic changes in seven patients (58%). Three patients showed extra copies of chromosome 21 including a case in which the trisomy 21 (+21) clone was distinct from the one harboring TEL/AML1 gene fusion. Interestingly, one patient without +21 showed amplification of the AML1 gene on chromosome 21q, supporting the contention that AML1 amplification may be an important additional genetic event. Gene expression study by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) in two of these four patients showed an increase in AML1 transcripts that paralleled the increase in gene copy number. Deletion of the normal TEL allele was detected in two patients, with one of them showing loss of chromosome 12 together with duplication of the der(12)t(12;21). Finally, one patient showed duplication of the fusion signal. Our findings confirm that additional or secondary genetic changes including AML1 amplification are commonly encountered in childhood ALL with TEL/AML1 gene fusion, which are envisaged to play significant roles in disease progression.

Adolescent↗
PubMed1999

TEL is a sequence-specific transcriptional repressor.

TEL is a gene frequently involved in specific chromosomal translocations in human leukemia and sarcoma that encodes a member of the ETS family of transcriptional regulators. TEL is unusual among other ETS proteins by its ability to self-associate in vivo, a property that is essential to the oncogenic activation of TEL-derived fusion proteins. We show here that TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven transcription of model and natural promoters. Deletion of the oligomerization domain of TEL or its substitution by the homologous region of monomeric ETS1 impaired the ability of TEL to repress. In contrast, substitution of the oligomerization domain of TEL by unrelated oligomerization domains resulted in an active repressor, showing that the ability of TEL to repress depends on its ability to self-associate. The study of the properties of TEL fusions to the heterologous DNA binding domain of Gal4 identified two autonomous repression domains in TEL, distinct from its oligomerization domain, that are essential to the ability of TEL to repress ETS-binding site-containing promoters. These results have implications for the normal function of TEL, its relation to other ETS proteins, and its role in leukemogenesis.

Animals↗
PubMed2002

TEL/AML1-positive pediatric leukemia: prognostic significance and therapeutic approaches.

This article presents the most recent insights into the biology, prognostic significance, and therapeutic approaches to TEL/AML1-positive leukemia. The TEL/AML1 fusion gene, also known as ETV6 /CBFA2, is the most commonly occurring gene rearrangement in pediatric acute lymphoblastic leukemia (ALL). Considerable controversy exists over its prognostic significance with currently available therapies. Differences in outcome may be explained by the differing intensities of various chemotherapy regimens, individual host responses to chemotherapy, or the hypothesis that relapsed TEL/AML1-positive leukemia represents an outgrowth of a secondary leukemia that shares a common initiating event with the first. Incorporating knowledge of this gene rearrangement into treatment decisions serves as a paradigm for translating molecular discoveries into clinically meaningful data to direct patient care and improve outcome.

Child↗