Abnormalities of the ETV6 gene occur in the majority of patients with aberrations of the short arm of chromosome 12: a combined PCR and Southern blotting analysis

O’Connor, Helen E.; Butler, Tina; Clark, Robin D.; Swanton, S; Harrison, Christine J.; Secker-Walker, LM; Foroni, Letizia

doi:10.1038/sj.leu.2401070

Cited by 31 publications

(21 citation statements)

References 13 publications

(24 reference statements)

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“…42 Following the identification of the TEL/AML1 gene rearrangement, it soon became clear that many of the deletions are often just secondary changes in these particular cases. 21,22,40,42,43 Moreover, it was found that they virtually always concur with the loss of the nontranslocated TEL allele. 40,42,43 Despite the fact that the TEL deletion may affect a variable proportion of TEL/AML1 rearranged cells, it is still considered as one of the most important cofactors to the development of overt leukemia.…”

Section: Discussionmentioning

confidence: 93%

“…21,22,40,42,43 Moreover, it was found that they virtually always concur with the loss of the nontranslocated TEL allele. 40,42,43 Despite the fact that the TEL deletion may affect a variable proportion of TEL/AML1 rearranged cells, it is still considered as one of the most important cofactors to the development of overt leukemia. 21,40,42,43 Accordingly, we detected a TEL deletion in 55% of the TEL/AML1 þ cases and found that it affected almost the entire TEL/AML1 þ blast cell population.…”

Section: Discussionmentioning

confidence: 93%

“…40,42,43 Despite the fact that the TEL deletion may affect a variable proportion of TEL/AML1 rearranged cells, it is still considered as one of the most important cofactors to the development of overt leukemia. 21,40,42,43 Accordingly, we detected a TEL deletion in 55% of the TEL/AML1 þ cases and found that it affected almost the entire TEL/AML1 þ blast cell population. However, as the particular TEL probe used was quite large, a number of small deletions may have been eventually missed.…”

Section: Discussionmentioning

confidence: 99%

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Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

Attarbaschi

Mann

König³

et al. 2004

Leukemia

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The aim of the present study was to determine the frequency and clinical relevance of the most common secondary karyotype abnormalities in TEL/AML1 þ B-cell precursor acute lymphoblastic leukemia (ALL) as assessed with fluorescence in situ hybridization (FISH) analyses. Screening of 372 patients who were enrolled in two consecutive Austrian childhood ALL multicenter trials identified 94 (25%) TEL/AML1 þ cases. TEL deletions, trisomy 21 and an additional der(21)t(12;21) were detected in 52 (55%), 13 (14%) and 14 (15%) TEL/AML1 þ patients, respectively. The 12p aberrations (P ¼ 0.001) and near tetraploidy (P ¼ 0.045) were more common in TEL/AML1 þ patients, whereas the incidence of diploidy, pseudodiploidy, hypodiploidy, low hyperdiploidy, near triploidy, del(6q), chromosome 9 and 11q23 abnormalities was similar among TEL/ AML1 þ and TEL/AML1À patients. None of the TEL/AML1 þ patients had a high hyperdiploid karyotype. Univariate analysis indicated that among TEL/AML1 þ patients those with a deletion of the nontranslocated TEL allele had a worse prognosis than those without this abnormality (P ¼ 0.034). We concluded that the type and incidence of the most common secondary aberrations in TEL/AML1 þ ALL can be conveniently identified with little additional effort during interphase screening with appropriate TEL and AML1 FISH probes. We also provided preliminary evidence that the deletion of the nontranslocated TEL allele may adversely influence the clinical course of TEL/AML1 þ ALL.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

Attarbaschi

Mann

König³

et al. 2004

Leukemia

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“…4,11,[30][31][32][33][34][35][36][37][38][39] Romana et al 30 first demonstrated that TEL-AML1 is the most common genetic alteration in childhood ALL, occurring in 23% of B-precursor cases. Importantly, the t(12;21) was not detected by conventional cytogenetics in any of these cases, underscoring the importance of molecular testing to identify this lesion.…”

Section: 29mentioning

confidence: 99%

The role of TEL fusion genes in pediatric leukemias

1999

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The TEL and AML1 genes are common targets of chromosomal translocations in hematopoietic malignancies. The TEL-AML1 fusion gene, created by the t(12;21), is the most common genetic alteration in childhood acute lymphoblastic leukemia and is associated with a favorable outcome. This review summarizes the roles of the TEL and AML1 proteins in hematopoiesis, the potential transforming mechanisms of TEL fusion proteins, and the clinical significance of the TEL-AML1 fusion.

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“…ETV6 is a member of the ETS family of transcription factors which may play a role in early hematopoiesis and angiogenesis (Baens et al, 1996;Edel, 1998;Kwiatkowski et al, 1998;O'Connor et al, 1998;Poirel et al, 1997;Wang et al, 1997Wang et al, , 1998. ETV6 was ®rst identi®ed as the fusion partner of PDGFRb in the t(5;12)(q33;p13) of chronic myelomonocytic leukemia (Golub et al, 1994), and has since been identi®ed in a variety of gene fusions associated with hematopoietic malignancies.…”

Section: Introductionmentioning

confidence: 99%

The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells

et al. 2000

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The congenital ®brosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 (TEL) gene on chromosome 12p13 in frame with the NTRK3 (TRKC) neurotrophin-3 receptor gene on chromosome 15q25. Resultant ETV6-NTRK3 fusion transcripts encode the helix ± loop ± helix (HLH) dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. We show here that ETV6-NTRK3 homodimerizes and is capable of forming heterodimers with wild-type ETV6. Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues. To determine if the fusion protein has transforming activity, NIH3T3 cells were infected with recombinant retroviral vectors carrying the full-length ETV6-NTRK3 cDNA. These cells exhibited a transformed phenotype, grew macroscopic colonies in soft agar, and formed tumors in severe combined immunode®cient (SCID) mice. We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation. To test this hypothesis, we expressed a series of ETV6-NTRK3 mutants in NIH3T3 cells and assessed their transformation activities. Deletion of the ETV6 HLH domain abolished dimer formation with either ETV6 or ETV6-NTRK3, and cells expressing this mutant protein were morphologically non-transformed and failed to grow in soft agar. An ATP-binding mutant failed to autophosphorylate and completely lacked transformation activity. Mutants of the three NTRK3 PTK activationloop tyrosines had variable PTK activity but had limited to absent transformation activity. Of a series of signaling molecules well known to bind to wild-type NTRK3, only phospholipase-Cg (PLCg) associated with ETV6-NTRK3. However, a PTK active mutant unable to bind PLCg did not show defects in transformation activity. Our studies con®rm that ETV6-NTRK3 is a transforming protein that requires both an intact dimerization domain and a functional PTK domain for transformation activity. Oncogene (2000) 19, 906 ± 915.

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Abnormalities of the ETV6 gene occur in the majority of patients with aberrations of the short arm of chromosome 12: a combined PCR and Southern blotting analysis

Cited by 31 publications

References 13 publications

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

The role of TEL fusion genes in pediatric leukemias

The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells

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