Novel BCR–ABL transcript containing an intronic sequence insert in a patient with Philadelphia‐positive acute lymphoblastic leukaemia

Hirota, Makoto; Hidaka, Eiko; Ueno, Ichiro; Ishikawa, Masayo; Asano, Naoki; Yamauchi, Kazuyoshi; Ishida, Fumihiro; Tozuka, Minoru; Katsuyama, Tsutomu

doi:10.1046/j.1365-2141.2000.02205.x

Cited by 7 publications

(5 citation statements)

References 12 publications

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“…In most of the cases, the inserted intronic sequence derived from ABL intron Ib (120.1 kb), [7][8][9][10][11] from ABL intron Ia (18.5 kb), 12,13 and more rarely from BCR intron 8 (10.2 kb).…”

Section: Resultsmentioning

confidence: 99%

“…15 Moreover, it should be noted that several studies described, in addition to a classical e13/a2, e14/a2, or e19/a2 mRNA, aberrant BCR-ABL transcripts harboring a frameshift insertion (3n ϩ 1 or 3n ϩ 2 nucleotides) disrupting the reading frame and leading to a premature stop codon ( Figure 4B). 7,16,17 Concerning rearrangements involving BCR exons out-of-frame with ABL exon a2 (or a3), an intronic insertion could restore the reading frame between the two coding sequences ( Figure 4C). As a consequence, the resulting BCR-ABL protein could then be functional.…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive Characterization of a Novel Intronic Pseudo-Exon Inserted within an e14/a2 BCR-ABL Rearrangement in a Patient with Chronic Myeloid Leukemia

Sorel

Mayeur-Rousse

Deverrière

et al. 2010

The Journal of Molecular Diagnostics

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We identified a novel breakpoint cluster region-ABL rearrangement in a chronic myeloid leukemia (CML) patient. The e14/a2 (b3/a2) type BCR-ABL mRNA incorporated a 42-nucleotide intronic insertion of ABL intron Ib between BCR exon e14 and ABL exon a2. As we hypothesized that the rearrangement between BCR and ABL genes occurred near the inserted sequence and because of the relative small size of BCR intron 14 , we determined the BCR-ABL breakpoint at the genomic DNA level. Using a PCR-based method, this analysis revealed that i) BCR intron 14 brought a potential lariat branch point and the polypyrimidine tract , ii) the BCR-ABL breakpoint created a chimeric acceptor site , and iii) the inserted sequence of ABL intron Ib carried at its 3 end a well-conserved donor splice site. Therefore , the inserted sequence was flanked by canonical consensus splice sites and recognized as a pseudo-exon (as shown by splice site prediction and exon finder software). Moreover, the insertion did not disrupt the reading frame between BCR and ABL and did not produce a premature stop codon. Instead , this novel BCR-ABL chimeric transcript encoded a functional oncoprotein with an in-frame insertion of 15 new amino acids. Philadelphia chromosome (Ph1) results from the reciprocal t(9;22)(q34;q11) translocation that fuses the BCR and ABL genes into a BCR-ABL chimeric gene, which encodes a constitutively activated tyrosine kinase oncoprotein.1 Breakpoints in ABL generally occur upstream of exon a2 (rarely exon a3). Depending on the location of the breakpoint in the BCR gene, three main types of BCR-ABL transcripts can be produced.2 In chronic myeloid leukemia (CML), most of the breakpoints in BCR occur in the 5.8-kb major breakpoint cluster region and result in the fusion at the mRNA level of BCR exon e13 (b2) or e14 (b3) to ABL exon a2, known as the e13/a2 or e14/a2 rearrangements. In Ph1-positive acute lymphoblastic leukemia, breakpoints in BCR are generally located in the minor major breakpoint cluster region and result in the e1/a2 BCR-ABL rearrangement. A third breakpoint in BCR (-BCR) is observed in typical CML or neutrophilic leukemia and leads to the e19/a2 rearrangement. Finally, e6/a2 and e8/a2 BCR-ABL rearrangements are uncommonly observed in typical CML. Thus, in the great majority of CML cases, BCR-ABL rearrangements result in the joining of BCR exons e13 or e14 to ABL exon a2.We report here a case of CML with an e14/a2 fusion mRNA containing a 42-bp sequence from ABL intron Ib inserted between BCR exon e14 and ABL exon a2. The insertion was characterized by sequencing at the mRNA level. The location of the BCR-ABL breakpoint was determined on genomic DNA, and the consensus donor and acceptor splice sites as well as a potential lariat branch point were identified. We demonstrated that, in this BCR-ABL rearrangement, the consensus splice sites were brought by BCR intron 14 (branch point and polypyrimiSupported by grants from the Ligue Contre le Cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Comprehensive Characterization of a Novel Intronic Pseudo-Exon Inserted within an e14/a2 BCR-ABL Rearrangement in a Patient with Chronic Myeloid Leukemia

Sorel

Mayeur-Rousse

Deverrière

et al. 2010

The Journal of Molecular Diagnostics

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“…Variant and complex Ph translocations are described (12). Novel BCR‐ABL transcripts with unusual breakpoints such as e19a2 or e1a3, or insertion of ABL sequences between BCR and ABL exons are found in rare cases (13, 14). The prognostic significance of these abnormalities is largely unclear (15).…”

Section: The Philadelphia Translocation and Its Molecular Correlatesmentioning

confidence: 99%

Philadelphia chromosome‐positive acute lymphoblastic leukemia– current concepts and future perspectives

Faderl

Garcia‐Manero

Thomas

et al. 2002

Rev Clin Exp Hematol

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Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is diagnosed rarely in children, but constitutes the most frequent cytogenetic abnormality in adults with ALL. In contrast to chronic myeloid leukemia (CML), patients with Ph-positive ALL usually demonstrate expression of a truncated version of the BCR-ABL protein called p190bcr-abl. Irrespective of age and breakpoint location, Ph-positive ALL carries a poor prognosis. Although remission rates are identical to those of Ph-negative ALL, relapse is almost universal and long-term survival remains rare. Given the poor outcome with current chemotherapy consolidation programs, stem cell transplantation is usually recommended for these patients in first remission or as soon as feasible. Even with transplantation the impact on outcome is limited and new therapeutic concepts are urgently needed. One of the most promising developments in recent years has been the introduction of the tyrosine kinase inhibitors such as STI571. An overview of current treatment modalities in Ph-positive ALL will be provided and the rationale for new therapies will be discussed.

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“…Summarized within are the variant BCR-ABL1 fusions that have been reported in Ph+ ALL to date (Table 1 (Tab. 1) ; References in Table 1: Soekarman et al, 1990[ 19 ]; Iwata et al, 1994[ 10 ]; Wilson et al, 2000[ 24 ]; Burmeister et al, 2007[ 3 ]; Fujisawa et al, 2008[ 8 ]; Langabeer et al, 2011[ 14 ]; Chen et al, 2013[ 5 ]; Shin et al, 2015[ 18 ]; Sonu et al, 2015[ 20 ]; López-Andrade et al, 2016[ 15 ]; Burmeister et al, 2007[ 3 ]; Zhang et al, 2016[ 25 ]; Kurita et al, 2016[ 13 ]; Hirota et al, 2000[ 9 ]; Burmeister et al, 2007[ 3 ]; Deshpande et al, 2016[ 7 ]; McCarron et al, 2011[ 16 ]; Kim et al, 2012[ 12 ]; Jeon et al, 2011[ 11 ]) and that result in the presence or absence of the encoded functional domains of the oncogenic BCR-ABL1 protein contributing to altered cellular adhesion, enhanced proliferation, inhibition of apoptosis and increased genomic instability of Ph+ ALL (Figure 1 (Fig. 1) ).…”

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confidence: 99%

Variant BCR-ABL1 fusion genes in adult Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

Langabeer

2017

EXCLI Journal; 16:Doc1144; ISSN 1611-2156

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Novel BCR–ABL transcript containing an intronic sequence insert in a patient with Philadelphia‐positive acute lymphoblastic leukaemia

Cited by 7 publications

References 12 publications

Comprehensive Characterization of a Novel Intronic Pseudo-Exon Inserted within an e14/a2 BCR-ABL Rearrangement in a Patient with Chronic Myeloid Leukemia

Comprehensive Characterization of a Novel Intronic Pseudo-Exon Inserted within an e14/a2 BCR-ABL Rearrangement in a Patient with Chronic Myeloid Leukemia

Philadelphia chromosome‐positive acute lymphoblastic leukemia– current concepts and future perspectives

Variant BCR-ABL1 fusion genes in adult Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

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