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Results for “ETS Translocation Variant 6 Protein”

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PubMed2002

Regression of congenital fibrosarcoma to hemangiomatous remnant with histological and genetic findings.

We report a rare case of congenital fibrosarcoma (CFS) showing regression during the course of disease, in which the histological and genetic alterations were investigated. This CFS, located on the patient's right hand, was a hemangiopericytomatous hypervascular tumor showing frequent mitosis and necrosis. Small lymphocytes, predominantly cytotoxic T cells and natural killer cells, infiltrated the tumor. At the age of 3 months, the patient received a partial resection of the tumor. At the age of 1 year, the hemangiopericytomatous tumor with a dilated vascular lumen remained, although most of the tumor cells exhibited focal necrosis with calcification and no mitotic activity. Lymphocytes increased in number and intermingled with the tumor cells. At the age of 4 years, vascular tissue consisting of inner endothelial cells and surrounding pericytomatous actin-positive cells remained at the previous tumor locus. With reverse transcription-polymerase chain reaction analysis, ETV6-NTRK3 fusion transcripts were detected in tumor samples at 3 months and at 1 year, but not from those at 4 years of age. These genetic and histological changes suggest that the CFS either completely disappeared by apoptosis or showed mature transformation to hemangiomatous tissue with aging.

Apoptosis↗
PubMed2002

Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201.

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

Binding Sites↗
PubMed1997

A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia.

The Janus family of tyrosine kinases (JAK) plays an essential role in development and in coupling cytokine receptors to downstream intracellular signaling events. A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 fusion protein includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain. TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.

Amino Acid Sequence↗
PubMed2004

Analysis of ETV6/RUNX1 fusions for evaluating the late effects of cancer therapy in ALL (acute lymphoblastic leukemia) cured patients.

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood. The improvements of therapies have increased the number of long-term survivors. However, an increased incidence of secondary neoplasias has been observed in this cohort. Our purpose was to evaluate the late effects of cancer therapy in cured patients previously treated for ALL, considering previous reports on the occurrence of gene fusions as putative markers of chromosomal instability. Twelve ALL patients (aged 5 to 16 years) and twelve healthy subjects (aged 18 to 22 years) were studied for the presence of ETV6/RUNX1 (TEL/AML1) translocations, which were detected by FISH (fluorescence in situ hybridization). The blood samples were collected months or years after completion of the therapy, and the frequencies of gene fusions in lymphocytes were compared with those obtained retrospectively for bone marrow samples at the time of diagnosis, and also for the control group. It was demonstrated that ETV6/RUNX1 gene fusion was a frequent event (0.59-1.84/100 cells) in peripheral blood lymphocytes from normal individuals and the ALL patients who underwent chemotherapy showed significantly (P = 0.0043) increased frequencies (0.62-3.96/100 cells) of the rearrangement when compared with the control groups (patients at diagnosis and healthy subjects). However, a significant difference was not found between the groups of patients at diagnosis and healthy subjects, when the two patients who were positive for the rearrangement were excluded. Therefore, increased frequencies of ETV6/RUNX1 fusions in ALL cured patients indicate the influence of previous exposure to anti-cancer drugs, and they may represent an important genetic marker for estimating the risk of relapse, or development of secondary neoplasias.

Adolescent↗
PubMedDate not supplied

Analysis of the TEL protein during tumour angiogenesis.

It has been proposed that breast cancer follows a programmed course of development that leads to an invasive phenotype that is associated with an increase in angiogenesis. Angiogenesis is a multistage process that requires, at its early stages, proliferation of endothelial cells, the break-down of their basement membranes, and their subsequent migration and organisation into new bud-like vascular structures. The regulation of endothelial cell proliferation and migration during angiogenesis involves the ETS family of transcription factors. The TEL gene is a member of the ETS family and may play a role in vessel formation. Vascular endothelial growth factor (VEGF) is a specific growth factor in new vessel formation and in this study its regulatory effects on TEL protein phosphorylation are detailed. The TEL protein is found to be expressed during early endothelial cell tube formation in vitro. However, smaller vessels in either tumour or ovarian angiogenesis did not express the transcription factor; only the larger mature vessels were positive. Interestingly, TEL protein expression was lost in the invasive breast carcinoma studied, whilst in normal breast tissue, hyperplasia and ductal carcinoma in-situ, TEL protein expression was seen. The loss of expression of TEL protein in invasive mammary gland carcinoma may be an important factor in the pathogenesis of breast carcinoma.

Breast Neoplasms↗
PubMed2003

Cerebral sinovenous thrombosis during asparaginase treatment. Case 3.

A boy (age: 7 1/2 years) with acute lymphoblastic leukaemia developed thrombosis of the sinus sagitalis superior with secondary haemorrhagic infarction while on induction treatment with vincristine, prednisone, and asparaginase. Based on this report, the potential pathogenic mechanisms are discussed with respect to congenital prothrombotic defects as well as to the role of antileukaemic treatment. Current hypotheses on mechanisms for thromboembolism in children and proposed prophylactic strategies are briefly summarized.

Antineoplastic Agents↗
PubMed2004

NQO1 C609T polymorphism in distinct entities of pediatric hematologic neoplasms.

BACKGROUND AND OBJECTIVES: NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that protects cells against mutagenicity from free radicals and toxic oxygen metabolites. The gene coding for NQO1 is subject to a genetic polymorphism at nucleotide position 609 (C-->T) of the human NQO1 cDNA. Heterozygous individuals (C/T) have intermediate activity and homozygotes for the variant allele (T/T) are deficient in NQO1 activity. In previous studies, genotypes conferring lower NQO1 activity have been associated with an increased risk of acute leukemia, particularly infant leukemia carrying MLL/AF4 fusion genes. In the present study, we investigated this association in our population and extended the analysis to other subgroups of pediatric hematologic neoplasms characterized by specific fusion genes. DESIGN AND METHODS: We genotyped 138 patients with childhood acute lymphoblastic leukemia (ALL) carrying distinct fusion genes (MLL/AF4=35; BCR/ABL=31; TEL/AML1=72), 71 cases of pediatric sporadic Burkitt's lymphoma and 190 healthy control individuals for the NQO1 C609T polymorphism. RESULTS: When compared to the healthy control group, only children with Burkitt's lymphoma significantly more often had NQO1 genotypes associated with lower NQO1 activity (odds ratio, 1.81; p=0.036), predominantly at a younger age (< 9 years at diagnosis: odds ratio, 3.02; p=0.003). INTERPRETATION AND CONCLUSIONS: Our results suggest that in our population the NQO1 C609T polymorphism does not confer an increased risk of the investigated entities of childhood ALL. However, there may be a modulating role for NQO1 in the pathogenesis of pediatric sporadic Burkitt's lymphoma.

Adolescent↗
PubMed2002

Multiplex RT-PCR assay for the detection of major fusion transcripts in Taiwanese children with B-lineage acute lymphoblastic leukemia.

BACKGROUND: The classification of B-lineage acute lymphoblastic leukemia (ALL) by specific chromosomal translocations may have prognostic implications. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay is a useful tool for the detection of fusion transcript resulting from specific chromosomal translocation of the leukemic cells. In general, fusion transcripts are determined individually, a process which is labor intensive in order to detect all major fusion transcripts. PROCEDURE: We use a multiplex RT-PCR assay to detect both the CML- and ALL-type BCR-ABL transcripts of the t(9;22), all described variants of the E2A-PBX1 transcripts of t(1;19), the MLL-AF4 transcripts of t(4;11), and all described variants of TEL-AML1 (also termed ETV6-CBFA2) of the cryptic t(12;21) in 165 leukemic samples at diagnosis. RESULTS: The study yielded a completely concordant result with those obtained by the individual RT-PCR assay. In this cohort of Taiwan children, the relative frequencies of the four translocations of B-lineage ALL were as following: 6% with ALL-type t(9;22)/BCR-ABL, 7% t(1;19)/E2A-PBX1, 3% t(4;11)/MLL-AF4, and 18% t(12;21)/TEL-AML1, comparable to those in the Western countries. CONCLUSION: Multiplex RT-PCR assay is an efficient, sensitive, accurate, and cost-effective diagnostic tool, which will likely improve our ability in accurately and rapidly risk-stratifying children with ALL.

Adolescent↗
PubMed2004

A 2-year-old with atypical CML with a t(5;12)(q33;p13) treated successfully with imatinib mesylate.

Atypical chronic myelogenous leukemia (aCML) is a myelodysplastic/myeloproliferative disorder that usually occurs in older adults. Here we report a pediatric patient with aCML and a t(5;12)(q33;p13) with a corresponding fusion gene ETV6-PDGFRB. Because the PDGFRB tyrosine kinase is one of the known targets of tyrosine kinase inhibitors, this patient achieved cytogenetic and molecular remission with treatment with imatinib mesylate (formerly STI571; now Gleevec in the United States and Glivec in Europe). This case illustrates one of many myelodysplastic/myeloproliferative disorders that can be treated with this particular tyrosine kinase inhibitor.

Benzamides↗
PubMed2000

Lineage specificity of CBFA2 fusion transcripts.

The CBFA2 gene on chromosome band 21q22 is one of the most commonly translocated genes in leukemia. As with other translocations, those involving CBFA2 are associated with specific disease phenotypes. Only one of the different translocations involving CBFA2, the t(12;21), has been associated with a non-myeloid lineage. Several different CBFA2 fusion transcripts were expressed in the myeloid 32Dcl3 cell line, and show that unlike the myeloid specific fusion transcripts, the lymphoid specific ETV6/CBFA2 transcript is not compatible with myeloid cell differentiation. It is shown that myeloid cells expressing the ETV6/CBFA2 transcript undergo apoptosis in response to a G-CSF differentiation signal. The molecular differences in the cells we studied are characterized using Western blot analysis to show that t(12;21) expressing cells fail to express the G-CSF receptor.

Acute Disease↗
PubMed1998

A multiplex RT-PCR assay for the detection of chimeric transcripts encoded by the risk-stratifying translocations of pediatric acute lymphoblastic leukemia.

Modern therapy for pediatric acute lymphoblastic leukemia (ALL) is based on the principle of risk stratification. One of the most important laboratory features used to accurately risk stratify patients is the presence of specific chromosomal translocation within the leukemic blasts. In this paper, we describe a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the accurate, sensitive, and rapid identification of chimeric transcripts encoded by the major risk-stratifying translocations of pediatric ALL. This assay will identify both the CML- and ALL-type BCR-ABL transcripts encoded by the t(9;22), all described variants of the E2A-PBX1 transcripts encoded by the t(1;19), the MLL-AF4 transcripts encoded by the t(4;11), and all variants of TEL-AML1 encoded by the t(12;21). In addition, we have developed a reverse dot-blot detection system as an alternative to traditional post-PCR Southern blot analysis. Application of this combined assay to the analysis of 70 leukemic samples and five cell lines resulted in a complete concordance between this multiplex assay and individual PCR reactions. The characteristics of the multiplex assay suggest that its application to routine clinical screening will significantly improve the ability of clinical laboratories to accurate risk stratify pediatric ALL patients.

Child↗
PubMed2002

ETV6/AML1 fusion by FISH in adult acute lymphoblastic leukemia.

Dual-color interphase fluorescence in situ hybridization (FISH) with ETV6 and AML1 probes was used for the first time on a series of 159 adult patients with acute lymphoblastic leukemia (ALL), for detection of the t(12;21)(p13;q22) translocation. Seven patients (4.4%) were found, with 50-100% of positive cells, of whom one of two tested, proved negative for the fusion product by RT-PCR. Two of them, aged 43 and 50 years, are the oldest patients so far confirmed to have the translocation. Three who relapsed at 10, 11 and 24 months, suggest that adults may not enjoy the good short-term prognosis reported for t(12;21)-positive children. Thirty-one-negative cases had signal numbers differing from the two expected for each gene. In 15 cases these results were consistent with the karyotype. In nine cases with uninformative cytogenetics, the numbers were consistent with those for centromeres and indicated a hidden aneuploidy. Loss of ETV6 genes in two cases and AML1 amplification in three others were not suspected from the cytogenetics. In conclusion, FISH proved to be reliable in defining ETV6/AML1 positivity in this group of patients as well as providing valuable insights into negative cases.

Adolescent↗
PubMed2004

High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias.

The t(12;21) translocation resulting in the TEL-AML1 gene fusion is found in 25% of childhood B-cell precursor (BCP) acute lymphoblastic leukemias (ALL). Since TEL-AML1 has been reported to induce cell cycle retardation and thus may influence somatic recombination, we analyzed 214 TEL-AML1-positive ALL by PCR for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. As a control group, 174 childhood BCP ALL without a TEL-AML1 were used. The majority of TEL-AML1-positive leukemias had a higher number of Ig/TCR rearrangements than control ALL. They also had a more mature immunogenotype characterized by their high frequency of complete IGH, IGK-Kde, and TCRG rearrangements. While IGK-Kde and TCRG were more frequently rearranged on both alleles at higher age, IGH and TCRD rearrangements decreased in their incidence along with a decrease in biallelic IGH rearrangements. This suggests that the recombination process continues in these leukemias leading to ongoing rearrangements and possibly also deletions of antigen receptor genes. We here provide first evidence that somatic recombination of antigen receptor genes is affected by the TEL-AML1 fusion, and that further age-related differences are probably caused by the longer latency period of the prenatally initiated TEL-AML1-positive leukemias in older children.

Adolescent↗
PubMed2000

Proteins of the ETS family with transcriptional repressor activity.

ETS proteins form one of the largest families of signal-dependent transcriptional regulators, mediating cellular proliferation, differentiation and tumorigenesis. Most of the known ETS proteins have been shown to activate transcription. However, four ETS proteins (YAN, ERF, NET and TEL) can act as transcriptional repressors. In three cases (ERF, NET and TEL) distinct repression domains have been identified and there are indications that NET and TEL may mediate transcription via Histone Deacetylase recruitment. All four proteins appear to be regulated by MAPKs, though for YAN and ERF this regulation seems to be restricted to ERKs. YAN, ERF and TEL have been implicated in cellular proliferation although there are indications suggesting a possible involvement of YAN and TEL in differentiation as well. Other ETS-domain proteins have been shown to repress transcription in a context specific manner, and there are suggestions that the ETS DNA-binding domain may act as a transcriptional repressor. Transcriptional repression by ETS domain proteins adds an other level in the orchestrated regulation by this diverse family of transcription factors that often recognize similar if not identical binding sites on DNA and are believed to regulate critical genes in a variety of biological processes. Definitive assessment of the importance of this novel regulatory level will require the identification of ETS proteins target genes and the further analysis of transcriptional control and biological function of these proteins in defined pathways.

3T3 Cells↗
PubMed2001

Quantification of TEL-AML1 transcript for minimal residual disease assessment in childhood acute lymphoblastic leukaemia.

Strategies currently used for residual disease detection in acute lymphoblastic leukaemia (ALL) rely on polymerase chain reaction (PCR) detection of immunoglobulin and T-cell receptor rearrangements. The TEL-AML1 fusion transcript, which is associated with t(12;21) (p13;q22), is found in 25% of childhood B-cell precursor ALL, and represents an interesting alternative target. We compared two methods for quantitating TEL-AML1 fusion transcripts: competitive PCR and real-time PCR. These techniques showed similar sensitivity (5 x 10(-5)) and reproducibility. Giving highly correlated results, both techniques can be conveniently used for TEL-AML1 transcript quantification. The constancy of TEL-AML1 expression was evaluated by measuring TEL-AML1 transcripts at different steps of the cell cycle, and in 21 cases of ALL at diagnosis. No major variation in TEL-AML1 expression was observed during the cell cycle or in 20/21 of the ALL patients. Residual disease was then determined after completion of induction therapy in 20 patients with a TEL-AML1-positive ALL. Seven patients out of 20 (35%) were still positive, including two patients with high level of residual blasts (close to or beyond 10(-2)). When comparison was possible, results obtained using TEL-AML1 quantification were in accordance with those obtained using T-cell receptor rearrangements analysis.

Child↗
PubMed2003

Real-time quantitative PCR: standardized detection of minimal residual disease in pediatric acute lymphoblastic leukemia. Polymerase chain reaction.

PURPOSE: To develop a standardized real-time polymerase chain reaction (PCR) method of quantifying minimal residual disease (MRD) in patients with pre-B acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In a series of 24 follow-up bone marrow (BM) samples in 11 patients (14 clonal markers), we performed real-time PCR assays using one consensus and one clone-specific primer for each marker. The markers analyzed included immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and TEL-AML1 rearrangements. RESULTS: We achieved a detection limit of 3.3 x 10(-5) +/- 1.2 x 10(-5) and an accurate quantitation (r = -0.99) limit of 2.0 x 10(-4) +/- 8.8 x 10(-5) blasts. Both inter- and intra-assay reproducibility were exceptional. Additionally, we found comparable results to those of a "gold standard" limiting-dilution PCR assay (r = 0.62). CONCLUSIONS: The IgH, TCR and TEL-AML1 markers can be used as targets by real-time PCR under the same cycling profile, allowing quantitation of MRD in more 95% of patients with pre-B ALL. This standardized, real-time PCR technique should simplify monitoring MRD in clinical trials.

Biomarkers, Tumor↗
PubMed2006

Gö6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells.

Aberrant activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling is implicated in a number of haematological malignancies and effective JAK inhibitors may be therapeutically useful. We found that Gö6976, an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC), inhibited interleukin 3/granulocyte-macrophage colony-stimulating factor-induced signalling, proliferation and survival whereas Gö6983, a broad spectrum PKC inhibitor, had no such effects. Gö6976 was found to be a direct and potent inhibitor of JAK2 in vitro. Gö6976 also inhibited signalling, survival and proliferation in cells expressing the leukaemia-associated TEL-JAK2 fusion protein and the myeloproliferative disorder (MPD)-associated JAK2 V617F mutant. In primary acute myeloid leukaemia (AML) cells, incubation with Gö6976 reduced constitutive STAT activity in all cases studied. In addition, Akt and mitogen-activated protein kinase phosphorylation were reduced in 4/5 FLT3-internal tandem duplication (ITD) positive AML cases and 7/13 FLT3-wild-type (WT) cases. Expression of FLT3-WT, ITD and D835Y in 32D cells showed that Gö6976 is also a potent inhibitor of WT and mutant FLT3. In AML cells, Gö6976 reduced the survival to 55 +/- 5% of control in FLT3-ITD cases and to 69 +/- 5% in FLT3-WT samples. These data may help identify clinically useful compounds based on the structure of Gö6976, which can be employed for the treatment of MPDs as well as AML.

Acute Disease↗