t(9;12)(q34;p13) ETV6/ABL1
2014-03-01 Etienne De Braekeleer , Etienne De Braekeleer , Etienne De Braekeleer Affiliation1.Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France
2.The Ohio State University, Division of Clinical Pathology, Department of Pathology, 167 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA
Clinics and Pathology
Disease
Malignant hemopathies (26 cases reported)
Phenotype stem cell origin
AML (3 cases), B-cell ALL (8 cases), T-cell ALL (1 case), RAEB evolving into AML (1 case), chronic myeloproliferative neoplasm (2 cases), Philadelphia chromosome-negative CML (11 cases).
Epidemiology
Gender: 17 males, 8 females; age at diagnosis: 8 months to 81 years.
Clinics
Eosinophilia appears to be a common feature of malignancies associated with the ETV6-ABL1 fusion gene (15/20 cases).
Note
The t(9;12)(q34;p13) involves the ETV6 gene (12p13), a transcription factor frequently rearranged in myeloid and lymphoid leukemias. More than 30 ETV6 fusion gene partners have been described. Most translocations involving ETV6 generate fusion genes that lead to the activation of transcription factors or kinases but other mechanisms are also known (loss of function of the fusion gene affecting ETV6 and the partner gene, activation of a proto-oncogene in the vicinity of a chromosomal translocation and dominant negative effect of the fusion protein over transcriptional repression mediated by wild-type ETV6).
Cytogenetics
Cytogenetics morphological
t(9;12)(q34;p13) is very difficult to be identified by conventional cytogenetics.
Cytogenetics molecular
t(9;12)(q34;p13) usually requires FISH analysis with ETV6 and ABL1 probes to be detected (cryptic translocation). Insertions are also frequently identified.
Additional anomalies
Additional anomalies are frequent but show no consistent features (trisomies and monosomies of various chromosomes, structural rearrangements including deletions and translocations).
Variants
t(9;12;14)(q34;p13;q22) (seen in conventional cytogenetics),
t(8;9;12)(p12;q34;p13) (seen in conventional cytogenetics),
ins(9;12)(q34;p13p13) (seen by molecular cytogenetics),
ins(12;9)(p13;q34q34) (seen by molecular cytogenetics).
t(8;9;12)(p12;q34;p13) (seen in conventional cytogenetics),
ins(9;12)(q34;p13p13) (seen by molecular cytogenetics),
ins(12;9)(p13;q34q34) (seen by molecular cytogenetics).
Genes Involved and Proteins
Gene name
ETV6 (ets variant 6)
Location
12p13.2
Note
The ETV6 gene encodes a transcription factor frequently rearranged in myeloid and lymphoid leukemias.
Dna rna description
The ETV6 gene spans a region of less than 250 kb at band 12p13.1 and consists of 8 exons. There are two start codons, one (exon 1a starting at codon 1) located at the beginning of the gene and another alternative (exon 1b starting at codon 43) upstream of exon 3.
Protein description
The ETV6 protein (452 amino acids) contains two major domains, the HLH (helix-loop-helix) and ETS domains. The HLH domain, also referred to as the pointed or sterile alpha motif domain, is encoded by exons 3 and 4 and functions as a homo-oligodimerization domain. The ETS domain, encoded by exons 6 through 8, is responsible for sequence specific DNA-binding and protein-protein interaction.
Gene name
ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location
9q34.12
Dna rna description
The ABL1 gene, spanning a 230-kb region at band 9q34, includes the 5 alternative first exons 1b and 1a and ten common exons numbered from 2 to 11. Alternative splicing using exons 1b and 1a gives rise to mRNA of 7 and 6 kb, respectively.
Protein description
The ABL1 protein has three SRC homology (SH) domains called SH1, SH2 and SH3, of which SH1 that has a tyrosine kinase function. The SH2 and SH3 domains are involved in protein-protein interactions, which regulate the tyrosine kinase activity; they are necessary for signal transduction function. The ABL1 protein has also three nuclear localization signal domains and three DNA binding regions and an F-actin binding domain.
Result of the Chromosomal Anomaly
Transcript
Two ETV6-ABL1 transcripts were identified in most of the patients, one joining exon 5 of ETV6 to exon 2 of ABL1, the other, usually found at very low levels, joining ETV6 exon 4 to ABL1 exon 2.
Schematic diagram of the ETV6, ABL1 and ETV6-ABL1 proteins.
Description
The fusion protein retains all three SH domains, including the tyrosine kinase domain, of ABL1, which make these patients sensitive to tyrosine kinase inhibitors. The retained N-terminal part of the ETV6 protein contains the helix-loop-helix domain necessary for oligomerization of the protein, which is required for tyrosine kinase activation, cytoskeletal localization and neoplastic transformation.
Oncogenesis
Constitutive tyrosine kinase activation of ABL1.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36485158 | 2022 | Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms. | 105 |
| 27229714 | 2016 | Characterization of leukemias with ETV6-ABL1 fusion. | 59 |
| 37454239 | 2023 | Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort. | 59 |
| 21102429 | 2011 | ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. | 56 |
| 33707599 | 2021 | Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan. | 51 |
| 35941390 | 2022 | Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia. | 42 |
| 28650474 | 2017 | An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia. | 35 |
| 27570624 | 2016 | A novel three-way rearrangement involving ETV6 (12p13) and ABL1 (9q34) with an unknown partner on 3p25 resulting in a possible ETV6-ABL1 fusion in a patient with acute myeloid leukemia: a case report and a review of the literature. | 34 |
| 37895201 | 2023 | Complex Genomic Rearrangements Involving ETV6::ABL1 Gene Fusion in an Individual with Myeloid Neoplasm. | 33 |
| 27812500 | 2016 | An ETV6-ABL1 fusion in a patient with chronic myeloproliferative neoplasm: Initial response to Imatinib followed by rapid transformation into ALL. | 32 |
| 24053143 | 2013 | Myeloproliferative neoplasm with ETV6-ABL1 fusion: a case report and literature review. | 31 |
| 38203288 | 2023 | ETV6::ABL1-Positive Myeloid Neoplasm: A Case of a Durable Response to Imatinib Mesylate without Additional or Previous Treatment. | 21 |
| 37503586 | 2023 | Myeloproliferative Neoplasm Driven by ETV6-ABL1 in an Adolescent with Recent History of Burkitt Leukemia. | 21 |
| 38952502 | 2024 | Mixed-phenotype (B-lymphocytic/myeloid) acute leukemia with ETV6-ABL1 expression. | 20 |
| 30028819 | 2019 | Cryptic ETV6-ABL1 Fusion and MLL2 Truncation Revealed by Integrative Clinical Sequencing in Multiply Relapsed Acute Lymphoblastic Leukemia. | 20 |
| 32299902 | 2021 | Myeloid/lymphoid neoplasms with eosinophilia/ basophilia and ETV6-ABL1 fusion: cell-of-origin and response to tyrosine kinase inhibition. | 17 |
| 39066837 | 2024 | ETV6::ABL1 fusion: from overlooked minor clone in myeloproliferative neoplasm to major player in leukemic transformation. | 15 |
| 21193423 | 2011 | ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition. | 12 |
| 30168245 | 2018 | A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings. | 12 |
| 29507076 | 2018 | Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. | 11 |
| 27834072 | 2017 | A Case of Chronic Myeloid Leukemia With Rare Variant ETV6/ABL1 Rearrangement. | 10 |
| 25368826 | 2014 | A cryptic ETV6/ABL1 rearrangement represents a unique fluorescence in situ hybridization signal pattern in a patient with B acute lymphoblastic leukemia. | 4 |
| 36068374 | 2023 | Updates on eosinophilic disorders. | 0 |
| 37283522 | 2023 | The international consensus classification of eosinophilic disorders and systemic mastocytosis. | 0 |
| 29726059 | 2018 | Two novel fusion genes, AIF1L-ETV6 and ABL1-AIF1L, result together with ETV6-ABL1 from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin. | 0 |
| 30948162 | 2019 | Eosinophilia in acute myeloid leukemia: Overlooked and underexamined. | 0 |
| 38441775 | 2024 | Characteristics and literature review of ETV6::ABL1 fusion gene-positive acute myeloid leukemia. | 0 |
| 39105739 | 2024 | Exploration of ETV6::ABL1-positive AML with concurrent NPM1 and FLT3-ITD mutations. | 0 |
| 29177615 | 2018 | ETV6-ABL1 fusion combined with monosomy 7 in childhood B-precursor acute lymphoblastic leukemia. | 0 |
| 36395310 | 2022 | Myeloid/Lymphoid Neoplasms with Eosinophilia and Platelet Derived Growth Factor Receptor Alpha (PDGFRA) Rearrangement. | 0 |
| 21435002 | 2011 | ABL1 fusion genes in hematological malignancies: a review. | 0 |
| 31425923 | 2019 | Chronic myelomonocytic leukemia with ETV6-ABL1 rearrangement and SMC1A mutation. | 0 |
| 33660258 | 2021 | Management of ETV6-ABL1-positive childhood acute lymphoblastic leukaemia: report of two cases, a literature review and a call for action. | 0 |
| 20073070 | 2010 | ABL1 rearrangements in T-cell acute lymphoblastic leukemia. | 0 |
| 23171811 | 2013 | Variant of ETV6/ABL1 gene is associated with leukemia phenotype. | 0 |
| 39138661 | 2025 | Correction to: ETV6::ABL1 fusion: from overlooked minor clone in myeloproliferative neoplasm to major player in leukemic transformation. | 0 |
| 30553471 | 2018 | Myeloproliferative neoplasm with ABL1/ETV6 rearrangement mimics chronic myeloid leukemia and responds to tyrosine kinase inhibitors. | 0 |
| 11170285 | 2001 | Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia. | 0 |
| 20589932 | 2010 | Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: poor prognosis and prenatal origin. | 0 |
| 32279331 | 2020 | Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. | 0 |
| 37551450 | 2023 | Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes: A workshop report with focus on novel entities and a literature review including paediatric cases. | 0 |
| 18656692 | 2008 | Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6/ABL1 rearrangement. | 0 |
| 24318592 | 2014 | Extramedullary T-lymphoid blast crisis of an ETV6/ABL1-positive myeloproliferative neoplasm with t(9;12)(q34;p13) and t(7;14)(p13;q11.2). | 0 |
| 38992279 | 2024 | ETV6::ABL1 positive myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) with blast crisis treated with flumatinib mesylate. | 0 |
| 39423354 | 2025 | Atypical chronic myeloid leukemia (CML) with ETV6-ABL1 mutation managed successfully with a third-generation TKI and hematopoietic stem cell transplant. | 0 |
| 39046810 | 2024 | How I (Diagnose and) Treat Myeloid / Lymphoid Neoplasms with Tyrosine Kinase Gene Fusions. | 0 |
| 22373549 | 2012 | Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. | 0 |
| 12823349 | 2003 | Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate. | 0 |
| 37985498 | 2024 | T cell phenotype and lack of eosinophilia are not uncommon in extramedullary myeloid/lymphoid neoplasms with ETV6::FLT3 fusion: a case report and review of the literature. | 0 |
| 20618334 | 2010 | A doctor(s) dilemma: ETV6-ABL1 positive acute lymphoblastic leukaemia. | 0 |
| 12161353 | 2002 | Clonal eosinophils are a morphologic hallmark of ETV6/ABL1 positive acute myeloid leukemia. | 0 |
| 27710957 | 2016 | Translocation (9;12)(q34.1;p13.?3) Resulted in ETV6-ABL1 Fusion in a Patient with Philadelphia Chromosome-Negative Chronic Myelogenous Leukemia. | 0 |
| 36624015 | 2023 | Clinical Response to Upfront Targeted Tyrosine Kinase Inhibitors among Patients with Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusion. | 0 |
| 18615681 | 2008 | Chronic phase of ETV6-ABL1 positive CML responds to imatinib. | 0 |
| 15789067 | 2005 | Broad molecular screening of an unclassifiable myeloproliferative disorder reveals an unexpected ETV6/ABL1 fusion transcript. | 0 |
| 28597942 | 2017 | Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9365838 | 1997 | BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. | Andreasson P et al |
| 8743990 | 1996 | Genomic organization of TEL: the human ETS-variant gene 6. | Baens M et al |
| 18656692 | 2008 | Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6/ABL1 rearrangement. | Baeumler J et al |
| 12823349 | 2003 | Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate. | Barbouti A et al |
| 22578774 | 2012 | ETV6 fusion genes in hematological malignancies: a review. | De Braekeleer E et al |
| 8754809 | 1996 | Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. | Golub TR et al |
| 18615681 | 2008 | Chronic phase of ETV6-ABL1 positive CML responds to imatinib. | Kawamata N et al |
| 19480935 | 2009 | Insertion (12;9)(p13;q34q34): a cryptic rearrangement involving ABL1/ETV6 fusion in a patient with Philadelphia-negative chronic myeloid leukemia. | Kelly JC et al |
| 12505259 | 2002 | Chronic myelocytic leukemia with eosinophilia, t(9;12)(q34;p13), and ETV6-ABL gene rearrangement: case report and review of the literature. | Keung YK et al |
| 12161353 | 2002 | Clonal eosinophils are a morphologic hallmark of ETV6/ABL1 positive acute myeloid leukemia. | La Starza R et al |
| 11840298 | 2002 | Detection of dual TEL-ABL transcripts and a Tel-Abl protein containing phosphotyrosine in a chronic myeloid leukemia patient. | Lin H et al |
| 20618334 | 2010 | A doctor(s) dilemma: ETV6-ABL1 positive acute lymphoblastic leukaemia. | Malone A et al |
| 11175368 | 2000 | Proteins of the ETS family with transcriptional repressor activity. | Mavrothalassitis G et al |
| 15789067 | 2005 | Broad molecular screening of an unclassifiable myeloproliferative disorder reveals an unexpected ETV6/ABL1 fusion transcript. | Meyer-Monard S et al |
| 17366548 | 2007 | A fifteen-year cytogenetic remission following interferon treatment in a patient with an indolent ETV6-ABL positive myeloproliferative syndrome. | Mozziconacci MJ et al |
| 19394693 | 2009 | Myeloproliferative disorder with eosinophilia and ETV6-ABL gene rearrangement: efficacy of second-generation tyrosine kinase inhibitors. | Nand R et al |
| 11964320 | 2002 | Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation. | O'Brien SG et al |
| 7805037 | 1995 | The novel activation of ABL by fusion to an ets-related gene, TEL. | Papadopoulos P et al |
| 21193423 | 2011 | ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition. | Perna F et al |
| 15676152 | 2005 | Molecular and cytogenetic characterization of a novel rearrangement involving chromosomes 9, 12, and 17 resulting in ETV6 (TEL) and ABL fusion. | Tirado CA et al |
| 11170285 | 2001 | Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia. | Van Limbergen H et al |
| 22373549 | 2012 | Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. | Zhou MH et al |
| 20589932 | 2010 | Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: poor prognosis and prenatal origin. | Zuna J et al |
Summary
Fusion gene
ETV6/ABL1 ETV6 (12p13.2) ABL1 (9q34.12) M ins(12;9)(p13;q34q34) ins(9;12)(q34;p13p13) t(9;12)(q34;p13) t(9;12;14)(q34;p13;q22)|ETV6/ABL1 ETV6 (12p13.2) ABL1 (9q34.12) TIC
Citation
Etienne De Braekeleer ; Etienne De Braekeleer ; Etienne De Braekeleer
t(9;12)(q34;p13) ETV6/ABL1
Atlas Genet Cytogenet Oncol Haematol. 2014-03-01
Online version: http://atlasgeneticsoncology.org/haematological/1080/t(9;12)(q34;p13)-etv6-abl1
Historical Card
2000-12-01 t(9;12)(q34;p13) ETV6/ABL1 by Nyla A Heerema Affiliation
The Ohio State University, Division of Clinical Pathology, Department of Pathology, 167 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA
