Acute leukemias with <i>ETV6/ABL1</i> (<i>TEL/ABL</i>) fusion: Poor prognosis and prenatal origin

Zuna, Jan; Žaliová, Markéta; Mužíková, Kateřina; Meyer, Claus; Lizcova, Libuse; Zemanová, Zuzana; Březinová, Jana; Votava, Felix; Marschalek, Rolf; Starý, Jan; Trka, Jan

doi:10.1002/gcc.20796

Cited by 38 publications

(50 citation statements)

References 37 publications

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“…Besides the involvement of ABL1, these cases have a similar profile of secondary aberrations including frequent deletions of IKZF1, CDKN2A/B, PAX5, BTG1 and RB1 which distinguish them from other ALL. [49][50][51] We have previously shown the prenatal origin of ETV6-ABL1 in a 5-year old child with ALL 20 demonstrating the need for cooperating mutations to induce an overt disease. The two most frequent secondary aberrations in ETV6-ABL1 ALL (CDKN2A/B and IKZF1 loss) have both been shown to cooperate with BCR-ABL1 during leukemogenesis in mice and likely represent cooperating lesions also in ETV6-ABL1 leukemia.…”

Section: Discussionmentioning

confidence: 97%

“…The cohort consisted of 44 patients with an ETV6-ABL1 fusion and comprised newly identified cases (n=9), published cases with additional new data (n=11) 7,8,[15][16][17][18][19][20] and cases with re-examined published data (n=24). 1,18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Standard diagnostics, including molecular genetics, karyotyping and fluorescence in-situ hybridization (FISH) were performed according to the standard practice of the local diagnostic laboratories.…”

Section: Patientsmentioning

confidence: 99%

“…The expression of alternative splice variants (type A/B) was detected by end-point reverse transcriptase polymerase chain reaction (RT-PCR) 20 and quantitative RT-PCR (qRT-PCR) analyses, utilizing forward primers annealing to ETV6 exon 5 (type B-specific: 5'-GCCCATCAAC-CTCTCTCATCG -3') or ETV6 exon 4/ABL1 exon 2 junction (type A-specific: 5'-CAGAACCATGAAGAA-GAAGCCC -3'). …”

Section: Detection Of Transcript Variantsmentioning

confidence: 99%

“…Meta-analysis of the data from four studies of adult ALL cases showed a frequency of 0.38% (4/1060). 18,20,39,42 One screening study in AML found a single case (1/1197) which coupled with the fact that only four ETV6-ABL1-positive AML cases have been published so far suggests that ETV6-ABL1 is very rare in AML. 18 Estimating the incidence of ETV6-ABL1 in MPN is difficult because no systematic screening data are available.…”

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confidence: 99%

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Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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T o characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

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Section: Discussionmentioning

confidence: 97%

Section: Patientsmentioning

confidence: 99%

Section: Detection Of Transcript Variantsmentioning

confidence: 99%

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confidence: 99%

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Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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“…[1][2][3][4][5][6][7][8][9] The ETV6-ABL1 fusion gene has also been identified in 3 patients with chronic myeloproliferative neoplasms other than "chronic myeloid leukemia" (cMPN) as well as 7 patients with BCR-ABL1 negative acute lymphoblastic leukemia and 4 patients with acute myeloid leukemia. 10,11 Of the 9 cases of ETV6-ABL1 + chronic myeloid leukemia, only 2 were treated with a TKI in chronic phase 4,5 and only one of these reached a complete remission with a modest follow up of seven months (no molecular monitoring was performed). 4 Among the other published ETV6-ABL1 + reports, one patient was treated with a second generation TKI for a relapsed cMPN.…”

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ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition

et al. 2010

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Technological Advances in the Detection of Novel Fusion Genes

Leow

Soo

et al. 2012

Encyclopedia of Life Sciences

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Since their first discovery in chronic myeloid leukaemia, fusion genes have been shown to play a central role in haematologic cancers. However, aberrations arising from this type of somatic mutations have been neglected in common solid tumours, largely because of limitations of current cytogenetic techniques. The recent discovery of recurrent gene fusions in prostate and lung cancer has led to a renewed interest in the identification of novel fusion genes in solid tumours. In this review, we discuss the technical challenges of studying gene fusions in solid tumours, appraise the application of newer molecular techniques and highlight emerging technologies, with the focus on next‐generation sequencing and chromogenic in situ hybridisation, that have greatly enhanced the speed and reliability of gene fusion discovery in malignant solid tumours. Key Concepts: A fusion gene is a gene hybrid formed from linking two physically separated genes. A fusion gene can occur as a result of chromosomal rearrangements such as translocations, insertions, deletions and inversions, which lead to novel protein fusion products. The detection of fusion genes is being recognised as a promising clinical tool for the diagnosis, staging classification, prognosis and treatment of cancer. Gene fusions have been an underappreciated class of mutation in solid tumours. The identification of gene fusions in solid tumours is technically challenging due to the complex and often chaotic karyotypic profiles of solid cancers. Recent advances in genomics obtained from next generation sequencing, coupled with the emerging field of bioinformatics and ever‐advancing molecular techniques, have uncovered many novel oncogenic fusion genes in solid tumours that were unable to be detected by traditional cytogenetic methods. Fluorescence In‐Situ Hybridisation (FISH) is recognised as the most effective diagnostic methods for the detection of gene fusions. Transcriptome‐sequencing (also known as RNA‐sequencing), a recently introduced high‐throughput method of characterising ribonucleic acid (RNA) transcribed from the genome is rapidly emerging as the key method for the discovery of gene fusions. Numerous challenges and unanswered issues remained with the discovery of novel gene fusions and their development as effective targeted cancer therapies or as clinical diagnostic and/or prognostic tools.

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Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: Poor prognosis and prenatal origin

Cited by 38 publications

References 37 publications

Characterization of leukemias with ETV6-ABL1 fusion

Characterization of leukemias with ETV6-ABL1 fusion

ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition

Technological Advances in the Detection of Novel Fusion Genes

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