e8a2 BCR–ABL: more frequent than other atypical BCR–ABL variants?

Demehri, Shadmer; Paschka, Peter; Schultheis, Beate; Lange, Thoralf; Sugimoto, Tsuneaki; Branford, Susan; Lim, Lay-Cheng; Kegel, Thomas; Martinelli, Giovanni; Hochhaus, Andreas; Druker, Brian J.; Deininger, MW

doi:10.1038/sj.leu.2403604

Cited by 32 publications

(38 citation statements)

References 7 publications

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“…13,42 Additional BCR-ABL fusion transcripts have been described, but they are rare or only reported once. 13,[17][18][19] Flow cytometric immunobead assay for detection of BCR-ABL fusion proteins F Weerkamp et al gene (splicing to exon 2 or exon 3), and because the M-bcr consists of two intronic regions (intron 13 and intron 14), a total of at least eight different frequently occurring fusion sites can be identified (Figure 1b). We attempted to raise antibodies against the tumorspecific fusion epitopes of the BCR-ABL proteins.…”

Section: Introductionmentioning

confidence: 99%

“…In addition several rare breakpoints have been reported (see arrows), including the v-bcr breakpoint. [17][18][19] (b) The three well-defined breakpoint regions in the BCR gene can produce at least eight different fusion transcripts, because of alternative splicing in the ABL gene (splicing to exon 2 or exon 3) and because the M-bcr consists of two intronic regions (intron 13 and intron 14). 13,42 Additional BCR-ABL fusion transcripts have been described, but they are rare or only reported once.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 In addition, several rare BCR-ABL variant fusion genes have been described, such as the variants that result in the p195, p200 and p225 BCR-ABL fusion proteins ( Figure 1). [17][18][19] The discovery that the BCR-ABL fusion proteins lead to an aberrantly increased signaling from the tyrosine kinase domain, 8,9,20,21 has stimulated research on small molecules to block this kinase activity. The development of Imatinib, a specific tyrosine kinase inhibitor, has greatly improved the therapeutic strategies to inhibit the oncogenic effects of the BCR-ABL protein.…”

Section: Introductionmentioning

confidence: 99%

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Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

Weerkamp

Dekking

et al. 2009

Leukemia

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BCR-ABL fusion proteins show increased signaling through their ABL tyrosine kinase domain, which can be blocked by specific inhibitors, thereby providing effective treatment. This makes detection of BCR-ABL aberrations of utmost importance for diagnosis, classification and treatment of leukemia patients. BCR-ABL aberrations are currently detected by karyotyping, fluorescence in situ hybridization (FISH) or PCR techniques, which are time consuming and require specialized facilities. We developed a simple flow cytometric immunobead assay for detection of BCR-ABL fusion proteins in cell lysates, using a bead-bound anti-BCR catching antibody and a fluorochromeconjugated anti-ABL detection antibody. We noticed protein stability problems in lysates caused by proteases from mature myeloid cells. This problem could largely be solved by adding protease inhibitors in several steps of the immunobead assay. Testing of 145 patient samples showed fully concordant results between the BCR-ABL immunobead assay and reverse transcriptase PCR of fusion gene transcripts. Dilution experiments with BCR-ABL positive cell lines revealed sensitivities of at least 1%. We conclude that the BCR-ABL immunobead assay detects all types of BCR-ABL proteins in leukemic cells with high specificity and sensitivity. The assay does not need specialized laboratory facilities other than a flow cytometer, provides results within B4 h, and can be run in parallel to routine immunophenotyping.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

Weerkamp

Dekking

et al. 2009

Leukemia

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“…14 It has been suggested that these types of rare rearrangements with a breakpoint in BCR exons occur more frequently in exon e8. 7 In our case, the breakpoint was identified in exon e13, and no third gene was found to be involved in gene rearrangement. However, it has not been determined whether the incorporation of novel sequence from either a previously non-coding intronic region or a third-party gene may confer any pathologic effect during tumorigenesis.…”

Section: Discussionmentioning

confidence: 92%

“…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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Molecular characterization and follow‐up of five CML patients with new BCR–ABL1 fusion transcripts

Huet

Dulucq

Chauveau

et al. 2015

Genes Chromosomes & Cancer

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We report five chronic myeloid leukaemia (CML) patients in whom we identified and characterized undescribed BCR-ABL1 fusion transcripts. We investigated the precise features of the molecular rearrangements and the minimal residual disease follow-up for these five patients. Three resulted from new rearrangements between the BCR and ABL1 sequences (the breakpoints being located within BCR exon 13 in two cases and within BCR exon 18 in one case). The other two cases revealed a complex e8-[ins]-a2 fusion transcript involving a third partner gene, PRDM12 and SPECC1L, respectively. Moreover, single nucleotide polymorphism-array analysis performed in the latter two cases showed copy number alterations shared by the two patients, thus identifying genes that were deleted during rearrangement and suggesting their potential role in CML pathogenesis. Interestingly, we highlight that the prognosis of alterations, such as the presence of an e8a2 transcript or the deletion of various genes, which have been controversial, may be definitively erased by the introduction of tyrosine kinase inhibitors (TKIs).

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e8a2 BCR–ABL: more frequent than other atypical BCR–ABL variants?

Cited by 32 publications

References 7 publications

Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

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

Molecular characterization and follow‐up of five CML patients with new BCR–ABL1 fusion transcripts

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