Acute myeloid leukemia carrying ETV6 mutations: biologic and clinical features
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Abstract:
Objectives: E26 transformation-specific variant 6 gene (ETV6) is one of the most consistently rearranged genes in acute leukaemia. It encodes a principal hematopoietic transcription factor.Methods: We performed a systematic review focusing on the mechanisms responsible for etv6 acquisition, and its effect on the development of AML. We also review the Characteristics of ETV6 mutations and its fusion genes. Finally, for using ETV6 as a molecular target, we discuss future therapeutic approaches available to mitigate the associated disease.Results: ETV6 rearrangements often accompany other molecular mutations. Thirty-three distinct partner bands of ETV6 that contain various fusion genes were detected which plays a vital role in obtaining information about leukaemia genesis. RXDX-101 and PKC412 were reported to be inhibitors of ETV6-NTRK3.Discussion: Future researches are needed to explain how ETV6 mutations act within the microenvironment of leukemic cells and how it affects the progression of leukaemia.Keywords:
ETV6
Rearrangements of 12p, resulting from deletions or translocations, are common findings in hematologic malignancies. In many cases, these rearrangements target the ETV6 gene (previously called TEL) located at 12p13. Various partner genes have been implicated in the formation of fusion genes with ETV6. These include PDGFRB, JAK2, NTRK3, ABL2, and ABL1, each of which encodes for proteins with tyrosine kinase activity. To date, ETV6/ABL1 transcripts have been detected in only four patients with a leukemic disorder. Here, we describe one adult with chronic myeloid leukemia and a child with T-cell acute lymphocytic leukemia with ETV6/ABL1. Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement. Molecular analysis showed the presence of two fusion transcripts in both patients as the result of alternative splicing, questioning the suggested role of these transcripts in the lineage specificity. Clinical findings of these patients were compared to those of previously reported cases, and the possible clinical and biological similarities between ETV6/ABL1 and other fusion genes leading to increased tyrosine kinase activity are discussed.
ETV6
PDGFRB
ABL
Gene rearrangement
Chimeric gene
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ETV6
Cosmid
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ETV6
ABL
Chimeric gene
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ETV6
Breakpoint
Chromosome 12
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ETV6::ABL1 gene fusion is a rare recurrent genomic rearrangement associated with hematologic malignancies, and frequently occurs with additional anomalies. Due to the opposite chromosome orientations of the ETV6 and ABL1 genes, an oncogenic in-frame ETV6::ABL1 gene fusion cannot be formed by a simple translocation. The molecular mechanism of the ETV6::ABL1 fusion and the significance of co-occurring anomalies are not fully understood. We characterized genomic alterations in an individual with ETV6::ABL1 gene-fusion-positive myeloid neoplasm using various genomic technologies. Our findings uncovered a molecular mechanism of the ETV6::ABL1 fusion, in which a paracentric inversion within the short arm of chromosome 12 (12p) and a translocation between the long arm of a chromosome 9 and the 12p with the inversion were involved. In addition, we detected multiple additional anomalies in the individual, and our findings suggested that the ETV6::ABL1 fusion occurred as a secondary event in a subset of cells with the additional anomalies. We speculate that the additional anomalies may predispose to further pathogenic changes, including ETV6::ABL1 fusion, leading to neoplastic transformation.
ETV6
ABL
Gene rearrangement
Chromosomal inversion
Fusion transcript
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Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET , ETV6-MAML3 , and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6 , RET , and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients’ age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET -targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B . The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non- ETV6 5′ fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
ETV6
Gene rearrangement
Fusion transcript
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Genetic analysis of high-grade glial tumors in children has revealed the presence of the ETV6-NTRK3 gene fusion in a small number of highly aggressive‐appearing neoplasms. Identification of this gene fusion is important in that these patients may benefit from new, targeted therapies. Clinical presentation, imaging, and pathologic confirmation were obtained from 5 patients with confirmed ETV6-NTRK3 gene fusion. This case series may raise awareness of this entity and prompt genetic evaluation.
ETV6
Presentation (obstetrics)
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ETV6
Gene rearrangement
Chimeric gene
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The MN1::ETV6 gene fusion resulting from t(12;22)(p13;q12) has been rarely reported in myeloid neoplasms. We describe a 69-year-old male with newly diagnosed acute myeloid leukemia (AML) with erythroid differentiation and t(12;22)(p13;q12) demonstrated by conventional chromosome studies. Subsequent fluorescence in situ hybridization studies demonstrated a balanced ETV6 gene rearrangement (at 12p13). To further characterize this translocation, whole-genome sequencing was performed which confirmed t(12;22) with breakpoints involving the MN1 and ETV6 genes. Herein, we describe our case and review the literature to summarize the clinical and laboratory findings in patients with this rare but recurrent MN1::ETV6 gene fusion observed in myeloid neoplasms. Importantly, this case expands the clinical spectrum associated with the MN1::ETV6 gene fusion to include AML with erythroid differentiation. Lastly, this case demonstrates the importance of moving toward more comprehensive molecular testing to fully characterize the driver events in neoplastic genomes.
ETV6
Fusion transcript
Gene rearrangement
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Objective:To investigate the expression of the fusion gene of ETV6-NTRK3 and its feature in hematological malignagcy;explore the relationship between the fusion gene and its immunophenotype;evaluate its value in the clinical dignosis,therapy and prognosis.Method:Collect 47 samples which were untreated and 14 samples of AML-M2 which were therapied by two courses with standard chemotherapy regimen,to amplify specific fusion gene fragment by RT-PCR method,flow cytometry was applied to analyze the immunophenotype of the 47 samples.Result:Under the ultraviolet light,two samples expressed ETV6-NTRK3 fusion gene among 47 samples.The positive rate was 14% in AML-M2(2/14).We could not detect any reciprocal products of NTRK3-ETV6.A nomal NTRK3 message was also undetectable.Conclusion:①About 14% AML-M2 can express ETV6-NTRK3 fusion gene t(12;15)(p13;q25).All of them are AML-M2a.②The present standard therapic program can not take any effect on the patients with ETV6-NTRK3 fusion gene;which is refractory leukemia,so the prognosis is badly.③According to the FCM immunophenotype analysis,the patients with ETV6-NTRK3 fusion gene expressed CD13 and CD33,and the expression of CD13 is stronger than that of CD33.No-CD14 expression.It signified the leukemic cell of the patients originated early,differentiated badly,and was high-grade malignancy.
ETV6
Immunophenotyping
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