Major molecular response to imatinib in a patient with chronic myeloid leukemia expressing a novel form of e8a2 BCR-ABL transcript

Tchirkov, Andréï; Couderc, Jacques; Perissel, B; Goumy, Carole; Régnier, Aline; Uhrhammer, Nancy; Verrelle, Pierre; Berger, Marc

doi:10.1038/sj.leu.2404012

Cited by 13 publications

(12 citation statements)

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“…Furthermore, some patients have atypical breakpoints, which are different from the above junctions. CML patients with different types of e8a2 BCR-ABL transcript have been reported [2,3,4,5,6]. In the current study, we identified a CML patient in the late chronic phase (CP) who possessed a novel e8a2 BCR-ABL transcript variant and her responses were followed during 65-month imatinib treatment.…”

Section: Introductionmentioning

confidence: 87%

“…In light of the fact that the direct junction between BCR exon 8 and ABL exon 2 results in the generation of a premature stop codon, an insertion of sequences or/and breakpoint within the BCR exon 8 is needed to produce an in-frame e8a2 transcript. Most reported inserted sequences were inverted partial ABL intron 1b [2,3,4,5,6]. Demrhi et al [2] reported 1 case with a 151-bp insertion from intron Ia.…”

Section: Discussionmentioning

confidence: 99%

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Imatinib Mesylate Resistance in a Chronic Myeloid Leukemia Patient with a Novel e8a2 BCR-ABL Transcript Variant

Qin

Jiang²,

Jiao³

et al. 2008

Acta Haematol

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Background: The vast majority of chronic myeloid leukemia (CML) patients express the BCR-ABL transcript with the b2a2 (e13a2) and/or b3a2 (e14a2) junctions. However, some rare cases have atypical breakpoints. Methods and Results: We identified a CML patient with a unique e8a2 BCR-ABL transcript variant. It contained the first 114 nucleotides of BCR exon 8, with an insertion of 16 nucleotides from the 3′ end of ABL intron 1a, followed by ABL exon 2. Due to her uncontrolled thrombocytosis after 3 years of interferon-α treatment, the patient received imatinib at a dosage of 400 mg/day. Though achieving a sustained and complete hematological response after 3 months, she was resistant to imatinib during the entire 65-month imatinib treatment. That is, she failed to achieve major cytogenetic response and there was no significant decrease in her BCR-ABL transcript levels. Meanwhile, an M351T mutant was detected at 18 months after the start of imatinib treatment. Conclusion: ABL point mutation is also a mechanism of imatinib resistance for CML patients with the BCR-ABL transcript variant.

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Section: Introductionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Imatinib Mesylate Resistance in a Chronic Myeloid Leukemia Patient with a Novel e8a2 BCR-ABL Transcript Variant

Qin

Jiang²,

Jiao³

et al. 2008

Acta Haematol

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“…The BCR exon 8 was most closely involved in such rearrangements with the identification of e8/intronic insertion/a2 BCR-ABL transcripts. To restore an artificial reading frame between BCR and ABL sequences, two mechanisms were mainly described: i) an intronic insertion of 3n ϩ 1 nucleotides between BCR exon e8 and ABL exon a2, 10,14 or ii) an intronic insertion within exon 8 (formation of an e8 partial/insertion/a2 rearrangement). [11][12][13] Concerning the e8/a2 rearrangement, the same ABL intron Ib inverted insertion has been reported in two CML cases.…”

Section: Resultsmentioning

confidence: 99%

“…The genomic sequence surrounding the BCR-ABL breakpoint was then analyzed using Human Splicing Finder 14) contributed to the polypyrimidine tract and an upstream potential branch point, whereas the ABL DNA sequence (intron Ib) brought a part of the acceptor site and a well-conserved splicing donor site. Consequently, the BCR-ABL rearrangement generated the recognition of an intronic sequence of 42 nucleotides derived from ABL intron Ib as a pseudo-exon.…”

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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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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“…1 These transcripts are well-characterized and frequently detected by screening methods based on real-time quantitative RT-PCR (qRT-PCR), which is considered as the gold standard for the diagnostic and follow-up examination of Ph positive leukemia due to its superior sensitivity and cost-effectiveness. 2 However, new and rare forms of BCR-ABL1 fusions have also been discovered and these novel fusion gene variants including those with a masked or undetermined Ph chromosome karyotyping, often cannot be identified by routine RT-PCR methods, [3][4][5][6][7][8][9][10][11][12][13][14][15] presenting a big challenge for conventional diagnostic approaches.…”

Section: Introductionmentioning

confidence: 99%

Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia

et al. 2016

Cancer Biology & Therapy

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Patients with BCR-ABL1 fusion genes are potential candidates for targeted therapy with tyrosine kinase inhibitor (TKI) imatinib. However, novel BCR-ABL1 fusion variants can be undetected by qRT-PCR-based routine molecular screening, affecting immediate patient management and proper treatment selection. In this study, we describe a case of chronic myeloid leukemia (CML) harboring a novel BCR-ABL1 variant gene. Although Fluorescent In situ Hybridization (FISH) analysis suggested Philadelphia (Ph) translocation, qRT-PCR screening failed to detect the presence of a functional fusion transcript, which is critical for selecting targeted therapy against BCR-ABL1 fusion with aberrant kinase activity. Meanwhile, G-band cytogenetic analysis was performed twice without a solid conclusion. To overcome the uncertainty whether TKIs should be used to treat this patient effectively, we performed whole genome sequencing (WGS) in a next-generation sequencing (NGS) platform and discovered an unusual e13a2-like BCR-ABL1 fusion with 9 ABL1 intron 1 nucleotides incorporated into the broken BCR exon 13 to form a novel chimeric exon, which has never been described previously based on the best of our knowledge. Based on FISH and NGS results, the patient was treated with imatinib, showing significant improvement. Moreover, we also detected novel genetic mutations in the known leukemic genes SETBP1, PAX5, and TP53, while their role in the leukemogenesis remains to be determined. In summary, we have identified BCR-ABL1 fusion and other genetic mutations in a diagnostically difficult case of CML, demonstrating that NGS is a powerful diagnostic tool when routine procedures are challenged.

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Major molecular response to imatinib in a patient with chronic myeloid leukemia expressing a novel form of e8a2 BCR-ABL transcript

Cited by 13 publications

References 4 publications

Imatinib Mesylate Resistance in a Chronic Myeloid Leukemia Patient with a Novel e8a2 BCR-ABL Transcript Variant

Imatinib Mesylate Resistance in a Chronic Myeloid Leukemia Patient with a Novel e8a2 BCR-ABL Transcript Variant

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

Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia

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