Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia

Zhou, Min‐Hang; Gao, Li; Yu, Jie; Xu, Yuanyuan; Ding, Yi; Wang, Nan; Wang, Wei; Li, Mian-Yang; Han, Xiaoping; Sun, Jingyang; Wang, Lili; Yu, Li

doi:10.1007/s00277-012-1431-4

Cited by 35 publications

(24 citation statements)

References 42 publications

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“…However, in three cases the type B fusion could have been missed due to the primers used for RT-PCR. 33,39 In the other case, the absence of ETV6 exon 5 in the expressed transcript was shown to result from direct disruption of this exon by a fusion-generating DNA break. 28 A chimeric kinase without ETV6 exon 5 lacks the GRB2 binding site and has attenuated oncogenic potential analogous to BCR-ABL1 deficient for GRB2 interaction.…”

Section: Discussionmentioning

confidence: 99%

“…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. Basic clinical/outcome data were collected from treating centers.…”

Section: Patientsmentioning

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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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: 99%

Section: Patientsmentioning

confidence: 99%

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Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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“…Median age was 26 years (range 1.5-80), with two children cases (one B-ALL and one T-ALL), and four cases were found in young adults (aged 25, 26, 32, 33) (Lacronique et al, 1997;Peeters et al, 1997;Najfeld et al 2007;Zhou et al, 2012).…”

Section: Epidemiologymentioning

confidence: 99%

t(9;12)(p24;p13) ETV6/JAK2

Huret¹

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…2 Since their original description, very few additional cases of hematologic malignancies with ETV6-JAK2 have been reported. 3 Later, additional translocations involving the JAK2 gene were identified, such as t(9;22)(q34;q11.2) leading to a BCR-JAK2 fusion, t(8;9)(p22;p24) leading to a fusion to the pericentrilar material 1 (PCM1) gene, or t(4;9)(q21;p24) fusing JAK2 to the SEC31A gene. [4][5][6] Interestingly, in all of the PCM1-JAK2 positive cases reported so far, large parts of JAK2 (exon 9) were included and associated with a wide disease phenotype spectrum, including atypical CML, myelodysplasia/-proliferation with erythroid hyperplasia, or T-cell lymphoma.…”

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Modeling ETV6-JAK2-induced leukemia: insights from the zebrafish

Schwaller

2012

Haematologica

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C loning and functional characterization of a large number of chromosomal translocations revealed that aberrant activation of protein kinases is a key event for expansion of the malignant clone in chronic myeloproliferative disorders, as well as in acute leukemia. The best known example is t(9;22)(q34;q11), leading to the expression of the BCR-ABL1 (BCR-ABL) tyrosine kinase fusion associated with chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). In 1997, two studies reported that the JAK2 gene on the short arm of chromosome 9p24 encoding for just another cytoplasmic protein tyrosine kinase is involved in rare chromosomal translocations resulting in fusions to the ETS-family member ETV6 (also known as TEL). Interestingly, particular breakpoints were found resulting in variant fusion proteins that were associated with different disease phenotypes. Peeters and colleagues cloned a t(9;12)(p24;p13) from a patient with early pre-B cell acute lymphoblastic leukemia (ALL) leading to a fusion of exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2, 4-17). In addition, they identified a t(9;15;12)(p24;q15;p13) in a patient with atypical CML in a transformation that fused exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2, 5-12).1 In parallel, Lacronique and colleagues cloned a t(9;12)(p24;p13) from blasts from a childhood T-cell ALL patient leading to a fusion of ETV6 exon 5 to JAK2 exon 19 containing only the JH1 tyrosine kinase domain (ETV6-JAK2, 5-19).2 Since their original description, very few additional cases of hematologic malignancies with ETV6-JAK2 have been reported. 3 Later, additional translocations involving the JAK2 gene were identified, such as t(9;22)(q34;q11.2) leading to a BCR-JAK2 fusion, t(8;9)(p22;p24) leading to a fusion to the pericentrilar material 1 (PCM1) gene, or t(4;9)(q21;p24) fusing JAK2 to the SEC31A gene. [4][5][6] Interestingly, in all of the PCM1-JAK2 positive cases reported so far, large parts of JAK2 (exon 9) were included and associated with a wide disease phenotype spectrum, including atypical CML, myelodysplasia/-proliferation with erythroid hyperplasia, or T-cell lymphoma. To address the biological activity of an ETV6-JAK2 fusion, several groups over-expressed the three fusion variants in IL-3 dependent murine Ba/F3 cells. Expression of all ETV6-JAK2 variants rendered Ba/F3 cells IL-3-independent with similar efficacy. Transformation of the cells by ETV6-JAK2 expression was associated with constitutive activation of the signal transducers and activators of transcription (STATs), predominantly of STAT5, but also STAT1 and STAT3, and expression of several putative STAT targets such as oncostatin M, CIS or PIM1. 8-10To model ETV6-JAK2 disease in vivo, we transplanted bone marrow cells with retroviral expression of the 5-19 fusion variant in lethally irradiated mice. All the mice developed an aggressive lethal mixed T-cell lympho-and myeloproliferative disease after a latency of 5-10 weeks. 8 Similarly, transgenic mice expressing the ETV6-JAK2 (5-19) variant from an SRα ...

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Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia

Cited by 35 publications

References 42 publications

Characterization of leukemias with ETV6-ABL1 fusion

Characterization of leukemias with ETV6-ABL1 fusion

t(9;12)(p24;p13) ETV6/JAK2

Modeling ETV6-JAK2-induced leukemia: insights from the zebrafish

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