Molecular cytogenetic characterization of rearrangements involving 12p in leukemia

Vieira, Luı́s; Marques, Bárbara; Cavaleiro, Carla; Ambrósio, Ana Paula; Jorge, Mariana Dias; Neto, Abrahão Hallack; Costa, José Jackson do Nascimento; Júnior, Esmeraldina; Boavida, Maria Guida

doi:10.1016/j.cancergencyto.2004.08.013

Cited by 7 publications

(5 citation statements)

References 21 publications

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“…The new version of the break-apart probe is designed to cover a broader area, to include a range of breakpoints in 12p13 within the ETV6 region. Heterogeneity in the breakpoint regions of both 12p13 and 7q36 has been previously reported [7,10,28]. This is obviously demonstrated once again in this report, where the variability not only in 12p13, but also in the 7q36 breakpoints is reiterated through the observation of the different patterns in different patients.…”

Section: Discussionsupporting

confidence: 82%

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

Naiel

Vetter²,

Plekhanova

et al. 2013

Cancers

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The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting.

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Section: Discussionsupporting

confidence: 82%

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

Naiel

Vetter²,

Plekhanova

et al. 2013

Cancers

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“…However, one signal in each case was produced by the same 5 0 cosmid probes of ETV6. In contrast, the second signals in the two fusion positive cases were the result of similar sized insertions into the long arm of chromosome 21, small enough to leave a residual green signal for ETV6 on the short arm of the der (12).…”

Section: Discussionmentioning

confidence: 81%

“…3,[6][7][8] Although ETV6 is an attractive candidate for the main target of the deletions and translocations associated with 12p, its central role remains unproven. 12 The fusion partners of ETV6, of which over twenty have been described, are either protein tyrosine kinases in which the majority of ETV6 breakpoints occur in intron 4 or 5 of the gene, or transcription factors of which the commonest is the fusion with RUNX1 in B-cell progenitor acute lymphoblastic leukaemia (BCP-ALL), with a breakpoint in intron 5. A third group of cases in which the 'fusion' does not always result in a meaningful protein product, has a breakpoint in intron 2.…”

Section: Introductionmentioning

confidence: 99%

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

Jalali

Konn

et al. 2007

Leukemia

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We describe four cases of childhood B-cell progenitor acute lymphoblastic leukaemia (BCP-ALL) and one of T-cell (T-ALL) with unexpected numbers of interphase signals for ETV6 with an ETV6-RUNX1 fusion probe. Three fusion negative cases each had a telomeric part of 12p terminating within intron 2 of ETV6, attached to sequences from 5q, 7p and 7q, respectively. Two fusion positive cases, with partial insertions of ETV6 into chromosome 21, also had a breakpoint in intron 2. Fluorescence in situ hybridisation (FISH), array comparative genomic hybridization (aCGH) and Molecular Copy-Number Counting (MCC) results were concordant for the T-cell case. Sequences downstream of TLX3 on chromosome 5 were deleted, leaving the intact gene closely apposed to the first two exons of ETV6 and its upstream promoter. qRT-PCR showed a significant upregulation of TLX3. In this study we provide the first incontrovertible evidence that the upstream promoter of ETV6 attached to the first two exons of the gene was responsible for the ectopic expression of a proto-oncogene that became abnormally close as the result of deletion and translocation. We have also shown breakpoints in intron 2 of ETV6 in two cases of insertion with ETV6-RUNX1 fusion.

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“…A bone marrow cell karyotype of the patient was established at diagnosis using standard cytogenetic procedures. Analysis of chromosome rearrangements including breakpoint localization was performed using fluorescence in situ hybridization (FISH) as previously described (Vieira et al, 2005). FISH probes included whole‐chromosome painting (WCP) probes for chromosomes 16, 20, and X (Cambio, Cambridge, United Kingdom) and several yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), and P1 artificial chromosome (PAC) probes mapping to the long arm of chromosome 20 (Table 1, Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

Three‐way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation

Vieira

Vaz

Matos

et al. 2012

Genes Chromosomes & Cancer

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Essential thrombocythemia (ET) is a myeloproliferative neoplasm essentially characterized by excessive production of platelets. Molecular pathogenesis of ET is linked in approximately half of the patients to intracellular cytokine signaling dysregulation as a result of thrombopoietin receptor or Janus kinase 2 (JAK2) mutations. However, genetic defects underlying cytokine transcription have not been associated with ET. Using molecular cytogenetics and whole-genome array analyses, we uncovered a submicroscopic deletion at 20q13.2 in a JAK2V617F-positive ET patient with an acquired complex chromosome translocation. The deletion encompassed the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene that encodes a transcription factor involved in the regulation of hematopoietic cytokines. RNA interference-mediated suppression of NFATC2 mRNA or pharmacological inhibition of NFATC2 protein with 11R-VIVIT in cultured JAK2V617F-positive SET-2 megakaryocytes increased colony stimulating factor 2 (granulocyte-macrophage) (CSF2) mRNA and promoted cell proliferation. Moreover, impairment of NFATC2-calcineurin interaction with 11R-VIVIT further reduced the transcription of the NFATC2 gene. Antibody-mediated neutralization of CSF2 cytokine in inhibitor-treated cells prevented 11R-VIVIT-induced cell proliferation, indicating that impairment of NFATC2-calcineurin interaction promotes megakaryocyte proliferation through up-regulation of CSF2 transcription. Our results suggest a model in which haplo-insufficiency of NFATC2 cooperates with activation of the JAK-STAT signaling pathway in the pathogenesis of JAK2V617F-positive ET with del(20q). These results further indicate that pathogenesis of ET may be linked to genetic defects of other transcription factor genes involved in the regulation of cytokine expression.

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Molecular cytogenetic characterization of rearrangements involving 12p in leukemia

Cited by 7 publications

References 21 publications

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

Three‐way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation

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