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Results for “ETS Translocation Variant 6 Protein”

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PubMed2002

Functional regulation of TEL by p38-induced phosphorylation.

TEL is a nuclear phosphoprotein that belongs to a member of the ETS family transcription factors. TEL acts as a tumor suppressor and is essential for establishing hematopoiesis in neonatal bone marrow. Because TEL possesses multiple putative mitogen-activated protein (MAP) kinase phosphorylation sites, we here investigated functional regulation of TEL via stress signaling pathways. We showed that TEL becomes phosphorylated in vivo by activated p38 but not by JNK1. The constitutive and inducible phosphorylation sites were found to be Ser(22) and Ser(257), respectively. TEL bound to p38 and was directly phosphorylated in vitro by p38. In vivo p38-dependent phosphorylation reduced trans-repressional abilities of TEL through ETS-binding consensus site. These data indicate that TEL's functions are potentially regulated by p38 which is activated by various kinds of stresses. TEL could be a constituent downstream of the specific MAP kinase in the signal transduction system.

Animals↗
PubMed2001

Involvement of the NF-kappaB pathway in the transforming properties of the TEL-Jak2 leukemogenic fusion protein.

Constitutively active tyrosine kinases are frequently expressed in various types of human leukemias as the result of chromosomal translocations. The TEL-Jak2 fusion oncoprotein possesses transforming properties in both animal and cellular models, that are tightly dependent on Stat5 activation. In the IL-3-independent TEL-Jak2-transformed Ba/F3 cells, activation of the PI-3K/Akt pathway appears essential to cell proliferation. Here we report a sustained activation of NF-kappaB factors in Ba/F3 cells, which inhibition dramatically impairs cell viability, indicating that NF-kappaB signaling exerts a major role in the anti-apoptotic activities of TEL-Jak2 oncoprotein.

Animals↗
PubMed2002

Different clones of t(1;12)/t(12;12) involving the ETV6 gene in a case of acute myeloid leukemia.

We describe here a case of a 77-year-old Japanese man who developed acute myeloid leukemia (AML-M2). Chromosome analysis of the bone marrow blast cells showed 46,XY,del(7q) at onset, and after relapse, two clones, 46,XY,t(1;12) and 46,XY,del(7q),t(12;12), were present. Fluorescence in situ hybridization analysis confirmed that each clone with the 12p abnormality involved the ETV6 gene. These findings suggest that the ETV6 gene rearrangements in this case were apparently independent of contribution to leukemogenesis, because this cytogenetic aberration appeared as a secondary change. To our knowledge, this is the first report of two different clones with ETV6 gene rearrangements in the same patient.

Aged↗
PubMed2003

A fluorescence in situ hybridization study of TEL-AML1 fusion gene in B-cell acute lymphoblastic leukemia (1984-2001).

Acute lymphoblastic leukemia (ALL) is associated with recurrent chromosomal abnormalities. The cryptic translocation t(12;21)(p13;q22), which leads to the TEL-AML1 fusion gene, is the most common abnormality in childhood B-cell ALL. The aim of this retrospective study was to determine the incidence of TEL-AML1 fusion in childhood and adult B-cell ALL using interphase fluorescence in situ hybridization (I-FISH) and its association with additional changes. FISH, using dual-color extra-signal (ES) DNA probe specific for the TEL and AML1 genes, was performed either on blast cells suspensions stored in liquid nitrogen immediately after Ficoll or on leukemic cells preserved in fixative solution at -20 degrees C after short-term culture. No TEL-AML1 fusion was observed in the 26 ALL adults. The fusion was found among 19.6% of the 57 ALL children, additional changes being identified by conventional cytogenetics in 80% of the cases. A deletion of the untranslocated TEL was observed in 36.3% of the ALL with the TEL-AML1 fusion. The coexpression of myelocytic and B-lymphoid antigens was found in 3 of the 11 of TEL-AML1 fusion positive-ALL. Our results (frequency of TEL-AML1 fusion in children and of the deletion of the untranslocated TEL allele, mean age of the patients and white blood cell count) are within the range observed by others. Structural chromosomal abnormalities other than the t(12;21) are frequent and may play a role in the prognosis of these patients.

Burkitt Lymphoma↗
PubMed1999

Augmentation of immune response by altered peptide ligands of the antigenic peptide in a human CD4+ T-cell clone reacting to TEL/AML1 fusion protein.

The 12;21 chromosomal translocation occurs in leukemic cells from 20(30% of patients with B-lineage childhood acute lymphoblastic leukemia, the result being the TEL/AML1 fusion gene carrying a sequence different from TEL or AML1. Because the protein newly formed by TEL/ AML1 fusion is probably not tolerated by human immune system, the fusion region is a good candidate for tumor antigen expressed only in TEL/ AML1-positive leukemic cells. We established two human CD4+ alphabeta T-cell clones (T31.1 and Y41.2) reacting to the TEL/AML1 fusion region, from two unrelated healthy donors. In order to do this, we stimulated peripheral blood mononuclear cells with synthetic peptides corresponding to the TEL/ AML1 fusion region. Both T31.1 and Y41.2 proliferated in response to TEL/ AML1 fusion protein as well as to a peptide IGRIAECILGMNPSR, in the context of HLA-DP5 and DP17, respectively, and killed B lymphoblastoid cells pulsed with the peptide. Furthermore, these T-cell clones proliferated in response to several altered peptide ligands carrying a single residue substitution in the TEL/AML1 peptide, and some induced augmentation of proliferation and production of Th1-type cytokines. These superagonistic altered peptide ligands can be given consideration for anti-leukemic immunotherapy.

Adjuvants, Immunologic↗
PubMed2005

Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

ADP-ribosyl Cyclase↗
PubMed2002

Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML.

The t(7;12)(q36;p13) is a recurrent abnormality in acute myeloid leukemia (AML) of childhood. The involved gene on chromosome 12 is TEL; the 7q36 partner gene has not been identified. We describe morphologic, molecular and cytogenetic characterization of two cases of 7q36/12p13-associated AML that provide important insights regarding the consequences of this rearrangement. First, the molecular organization of the breakpoint regions differ significantly: one case is a reciprocal 7;12 translocation (RTR); the other has an insertion of 7q into 12p (INS). While 12p13 breakpoints in both patients interrupt TEL intron 1, the centromere to telomere orientation of the 7q36 sequences relative to the TEL sequences are inverted in INS compared to RTR. This difference makes it difficult to postulate a mechanism whereby both patients could produce a common fusion transcript. Further, no evidence was obtained for any TEL-containing fusion transcripts. Finally, we report the first cloning of a 7;12 genomic breakpoint (from RTR) and find that it maps to a site 30 kbp proximal to the HLXB9 gene in 7q36. Together, these data suggest that, unlike most leukemia-associated chromosomal rearrangements, the important consequence of the t(7;12) is likely not the generation of a novel fusion transcript, but instead the inactivation of TEL and/or a gene at 7q36.

Base Sequence↗
PubMed2004

A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase.

A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (Deltae5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and Deltae5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation.

TEL is an ETS family transcription factor that possesses multiple putative mitogen-activated protein kinase phosphorylation sites. We here describe the functional regulation of TEL via ERK pathways. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). TEL binds to a common docking domain in ERK. In vivo ERK-dependent phosphorylation reduces trans-repressional and DNA-binding abilities of TEL for ETS-binding sites. A mutant carrying substituted glutamates on both Ser(213) and Ser(257) functionally mimics hyperphosphorylated TEL and also shows a dominant-negative effect on TEL-induced transcriptional suppression. Losing DNA-binding affinity through phosphorylation but heterodimerizing with unmodified TEL could be an underlying mechanism. Moreover, the glutamate mutant dominantly interferes with TEL-induced erythroid differentiation in MEL cells and growth suppression in NIH 3T3 cells. Finally, endogenous TEL is dephosphorylated in parallel with ERK inactivation in differentiating MEL cells and is phosphorylated through ERK activation in Ras-transformed NIH 3T3 cells. These data indicate that TEL is a constituent downstream of ERK in signal transduction systems and is physiologically regulated by ERK in molecular and biological features.

Animals↗
PubMed2006

CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia.

PURPOSE: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome. EXPERIMENTAL DESIGN: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples. RESULTS: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP- group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP- group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples. CONCLUSION: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.

Adolescent↗
PubMed2002

Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation.

We report the transient response of a patient with the ETV6-ABL fusion gene to imatinib mesylate (STI571). A 38-year-old man was referred with an erroneous diagnosis of Philadelphia-positive chronic myeloid leukemia in blastic transformation for treatment with the ABL tyrosine kinase inhibitor, STI571. Further investigation indicated that the patient in fact had acute myeloid leukemia; no evidence of the Philadelphia translocation or BCR-ABL was found using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction. Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript. Because the patient was gravely ill at presentation, treatment was commenced immediately with STI571 monotherapy, resulting in considerable initial improvement. However within 10 days the patient's condition again deteriorated, and he required conventional chemotherapy. This case has implications for the design of future studies using STI571 in leukemias involving ABL-encoded fusion proteins other than BCR-ABL.

Acute Disease↗
PubMed2002

TEL-AML1, expressed from t(12;21) in human acute lymphocytic leukemia, induces acute leukemia in mice.

TEL-AML1 is expressed from the t(12;21) chromosomal translocation inB-precursor acute lymphocytic leukemia (ALL). Creation of the TEL-AML1fusion disrupts one copy of the TEL and AML1 genes, and loss of TEL or AML1 is also associated with cases of acute leukemia without TEL-AML1. To determine whether TEL-AML1 can contribute to leukemogenesis, we transduced marrow from C57BL/6 mice with a retroviral vector expressing TEL-AML1 or with a control vector. Transduced cells were introduced into irradiated syngeneic recipients. Two of 9 TEL-AML1 mice developed ALL (one T-lineage ALL and one B-precursor ALL), whereas 0 of 20 control mice developed leukemia. The B-precursor ALL was retransplantable and expressed TEL-AML1. We similarly transduced marrow from C57BL/6 mice lacking the overlapping p16(INK4a)p19(ARF) genes and transplanted the cells into wild-type recipients. No control mice died, but six of eight TEL-AML1/p16p19 mice died with leukemia. Overall, these findings indicate that TEL-AML1 contributes to leukemogenesis and may cooperate with loss of p16(INK4a)p14(ARF) to transform lymphoid progenitors.

3T3 Cells↗
PubMed2006

Fusion of ETV6 to GOT1 in a case with myelodysplastic syndrome and t(10;12)(q24;p13).

The ETV6 gene on 12p13 is involved in different hematologic malignancies through a variety of chromosomal translocations. Here we report the analysis of a t(10;12)(q24;p13) identified in a patient with myelodysplastic syndrome. Our results show that the t(10;12) results in the generation of an in-frame fusion between ETV6 and GOT1, a gene encoding a cytosolic glutamic-oxaloacetic transaminase enzyme. In addition, two other fusion transcripts involving exons from yet unidentified genes were detected, as well as expression of an uncharacterized gene from the 10q24 region. This work identifies GOT1 as a novel fusion partner of ETV6 in myelodysplastic syndrome.

Aged↗
PubMed2006

[Immunophenotypic characteristics of children with acute lymphoblastic leukemia carrying TEL-AML1 fusion gene].

To investigate the immunological and other clinical characteristics in TEL/AML1+ childhood B-acute lymphoblastic leukemia (B-ALL), immunophenotyping was performed with three-color flow cytometry, and the expression of TEL-AML1 fusion gene was detected with nested RT-PCR. Diagnosis was made according to FAB and MIC criteria. The results showed that (1) among 119 children with B-ALL, 22 (18.5%) were TEL-AML1 positive and classified as L2 morphological subtype. In TEL-AML1+ group, positive rate and score of PAS, which were 65% and 121 respectively, were all higher than that of TEL-AML1- group (P < 0.05); (2) compared with TEL-AML1- group, no significant difference was found in age, gender, white cell count and blasts count in peripheral blood of TEL-AML1+; (3) in TEL-AML1+ group, 21 out of 22 (95.5%) were common ALL, as compared with TEL-AML1- group, the positive rate of CD13 was higher (59.1%, 13/22) and the positive rate of CD20 was lower (22.7%, 5/22) than that in TEL-AML1- group, respectively (P < 0.05), and the mean fluorescence index of CD10 and HLA-DR significantly increased to 92.80 and 53.61, respectively (P < 0.05). It is concluded that TEL-AML1 rearrangement is a frequent molecular abnormality in childhood ALL. Leukemic blasts with this anomaly have special immunophenotypic characteristics. These characteristics may be useful in detection of minimal residual leukemia.

Antigens, CD20↗