Detection of E2A translocations in leukemias via fluorescence in situ hybridization

Boomer, Theresa; Varella-Garcia, M.; McGavran, Loris; Meltesen, Lynne; Olsen, Anne S.; Hunger, SP

doi:10.1038/sj.leu.2401988

Cited by 28 publications

(35 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Each split-signal FISH probe set consists of two differentially labeled probes (generally composed of several BAC/PAC clones), which are located in the target gene at opposite sides of the breakpoint region. [34][35][36]56 All six probe sets are directly labeled and work smoothly in combination with the newly developed PNA-blocking system, which allows combined blocking and hybridization in a single step. This singlestep hybridization procedure makes split-signal FISH an easy, rapid, and sensitive tool for molecular cytogenetics (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…54,63 Two probes were designed (TCF3-U and TCF3-D), which flank the breakpoint region without overlapping it. 56 In cases without a translocation, two colocalized signals will be present (Figure 4b and c). A balanced translocation involving the TCF3 (E2A) gene results in split of one of the colocalized signals giving rise to one separate green signal and one separate red signal, together with a fusion signal of the unaffected chromosome (Figure 4d).…”

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 97%

“…[53][54][55] In the remaining cases, the TCF3 (E2A) and PBX1 genes are not involved and therefore this translocation is referred to as a E2A-PBX1-negative t(1;19). 56 The E2A-PBX1 fusion protein is able to transform cells by constitutive activation of genes, which are normally regulated by PBX1 or other members of the PBX1 protein family. In addition, the leukemogenic effect of t(1;19)(q23;p13) might also result from a reduced level of wild-type E2A protein, which has recently been shown to have antiproliferative capacity in B-cell progenitors.…”

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 99%

“…This TCF3 (E2A) probe set has been proven to detect translocations t(1;19) and t(17;19) and should theoretically also detect inv (19), although due to their rarity ALL samples bearing such aberrations have not yet been analyzed. 56 …”

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 99%

See 3 more Smart Citations

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Burg

Poulsen²,

Hunger

et al. 2004

Leukemia

View full text Add to dashboard Cite

Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusionsignal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity. Leukemia ( Chromosome aberrations play an important role in hematological malignancies. 1 In ALL, most of these aberrations concern balanced translocations involving genes that play key roles in the development and function of lymphoid cells, such as transcription factors, cell cycle regulators, and signal transduction molecules. Balanced translocations can result in fusion of two genes that encode leukemia-specific chimeric (fusion) proteins. The fusion proteins have functional features that differ from the corresponding wild-type proteins and mostly play a role in leukemogenesis. In addition to the new features of the fusion protein, loss of wild-type activity due to the translocation (in some translocations enhanced by deletion of the second allele) might contribute to oncogenesis. Alternatively, chromosome translocations can result in deregulated expression of (onco)genes as a direct consequence of a translocation to a regulatory element, for example, an immunoglobulin (Ig) or T-cell receptor (TCR) enhancer. 2,3 The most frequent translocations in precursor-B-ALL are t(1;19)(q23;p13) t(4;11)(q21;q23), t(12;21)(p13;q22), and t(9;22)(q34;q11), all four of which result in generation of fusion genes. The t(1;19)(q23;p13) fuses the transcription factorencoding gene TCF3 (E2A) with the transcription factor PBX1. In t(4;11)(q21;q23), the MLL gene at 11q23, which encodes a putative DNA-binding protein, is translocated to the MLLT2 (AF4) gene. The MLL gene is involved in many other translocations in ALL and acute myeloid leukemia (AML). Until now, more than 30 partner genes have been identified. 4 The t(12;21)(p13;q22) involves th...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 97%

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 99%

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 99%

See 2 more Smart Citations

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Burg

Poulsen²,

Hunger

et al. 2004

Leukemia

View full text Add to dashboard Cite

show abstract

“…The BAC DNAs were prepared with a Qiagen Large Construction Kit (Qiagen) and labelled with SpectrumGreenconjugated dUTPs (RG331N4, RP23-6A14 and RP23-357G5 on chromosome 14) or SpectrumRed-conjugated dUTPs (RP23-98D8, RP24-194H23 and RP23-55P19 on chromosome 15) using the Vysis Nick Translation Kit (Abbott Molecular), in accordance with the manufacturers' instructions. Single-colour and dual-colour FISH assays were performed as described previously 27 . FISH images were captured with a charge-coupled device camera under a Zeiss Axio Imager Z1 fluorescence microscope equipped with proper filters (Zeiss).…”

Section: Sky and Fish Analysismentioning

confidence: 99%

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Guo¹,

Lasky²,

Chang³

et al. 2008

Nature

222

261

View full text Add to dashboard Cite

Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance 1 . The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit mid CD3 + Lin − compartment, where unphosphorylated β-catenin is significantly increased. Conditional ablation of one allele of the β-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the β-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit mid CD3 + Lin − LSCs and CD3 + leukaemic blasts,

show abstract

Formation of der(19)t(1;19)(q23;p13) in acute lymphoblastic leukemia

Paulsson

Horvat

Fioretos

et al. 2004

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)- and der(19)-positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)-both copies of a chromosome being derived from only one parent-for chromosome 1 would be present in all der(19)-harboring cases arising via the duplication pathway and in one-third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)- and four der(19)-positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1.

show abstract

Detection of E2A translocations in leukemias via fluorescence in situ hybridization

Cited by 28 publications

References 29 publications

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Formation of der(19)t(1;19)(q23;p13) in acute lymphoblastic leukemia

Contact Info

Product

Resources

About