A rare e14a3 BCR/ABL fusion transcript in acute lymphoblastic leukemia patient treated with CAR-modified T-cell therapy

Cai, Haodong; Yang, Li; Shen, Kefeng; Zhang, Wei; Xiong, Jie; Zhang, Meilan; Mao, Xia; Wang, Ying; Xiao, Min

doi:10.3892/ol.2017.7611

Cited by 5 publications

(4 citation statements)

References 9 publications

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“…In the present report we describe the clinical history of a very elderly CML patient with the t(9;22) reciprocal translocation detected by G-banding encoding for a rare e13a3 BCR-ABL1 transcript. Although individual accounts of single patients exhibiting BCR-ABL1 transcripts lacking exon 2 of ABL1 have been previously published (21)(22)(23), to the best of our knowledge this is the first case reporting the occurrence of this unusual fusion in a very elderly individual treated with a second-generation TKI. Uncommon BCR-ABL1 isoforms can go undetected since the classical RT-PCR multiplex employed to diagnose the disease can sometimes generate atypical PCR fragments often interpreted as nonspecific products.…”

Section: Discussionmentioning

confidence: 89%

Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3 Bcr-Abl1 Fusion Transcript: A Case Report

et al. 2019

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We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.The Philadelphia Chromosome (Ph) is generated by a reciprocal translocation t(9;22) (1, 2) leading to the assembly of a chimeric BCR-ABL1 oncogene that modulates the proliferation, apoptotic rate, cytoskeletal dynamics and microenvironment interaction of the hematopoietic stem cell, thereby giving rise to chronic myeloid leukemia (CML) (3-7). Usually, the BCR-ABL1 fusion encompasses exon 2 of the ABL1 gene that is fused in frame with one of three different breakpoints on the BCR gene: i) major (M-BCR), ii) minor (m-BCR) and iii) micro (μ-BCR). M-BCR includes the fusion transcripts in proximity of exons 13 or 14 of BCR, generating the more common e13a2 or e14a2 BCR-ABL1 variants. The remaining m-BCR and μ-BCR breakpoint clusters involve less common rearrangements affecting exons 1 or 19 of BCR that generate the e1a2 (8) or e19a2 fusions, respectively (9). Moreover, additional uncommon breakpoints have been previously described involving BCR exons 6 and 8 or ABL1 exon 3 (10). Interestingly, BCR-ABL1 isoforms involving exon 3 of ABL1 (e13a3, e14a3 and e19a3) have been described both in CML patients (11-13), with contrasting clinical outcomes, and in individuals diagnosed with Ph+ acute lymphoblastic leukemia ( 14). In the present study we report the case of a very elderly CML patient expressing a rare e13a3 BCR-ABL1 transcript displaying a partially satisfactory response to dasatinib (DAS) treatment.

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Section: Discussionmentioning

confidence: 89%

Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3 Bcr-Abl1 Fusion Transcript: A Case Report

et al. 2019

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“…We therefore decided to employ primers recognizing more distant exons from the common BCR-ABL1 breakpoints and successfully identified the atypical BCR-ABL1 e14a3 rearrangement. To date, different cases of CML patients expressing this isoform have been reported (16,21,23,24). Although IM represents an excellent first line therapy for most CML patients (7), extensive published data suggest that patients receiving this drug may more frequently develop both BCR-ABL-dependent and BCR-ABL-independent resistance to therapy (8,19,25) requiring alternative treatments (26).…”

Section: Discussionmentioning

confidence: 99%

Rapid decline of Philadelphia‑positive metaphases after nilotinib treatment in a cml patient expressing a rare e14a3 bcr‑abl1 fusion transcript: A case report

et al. 2019

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We report a case of chronic myeloid leukemia in a 52-year-old male expressing a rare e14a3 BCR-ABL1 fusion transcript. Cytogenetic analysis showed the t(9;22) translocation and multiplex RT-PCR detected an atypical fragment of approximately 230 base pairs. Using two primers recognizing exon 10 of BCR and exon 4 of ABL1, a larger PCR product was identified, cloned, sequenced and defined as an e14a3 BCR-ABL1 rearrangement. The patient was treated with nilotinib and monitored measuring cytogenetic and hematological parameters, while BCR-ABL1 transcripts were surveyed by conventional and semi-nested PCR. The patient achieved a complete hematologic response after two months of treatment followed by a complete cytogenetic remission two months later. Furthermore, PCR and semi-nested PCR failed to detect the e14a3 BCR-ABL1 mRNA after 15 and 21 months of nilotinib, respectively.

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“…As early as 20 years ago, it was used for sequencing Ig heavy-chain genes of chronic lymphoblastic leukemia patients ( Rosenwald et al., 2001 ). In addition, the fusion of BCR e14 and ABL a3 with or without any extra insertions or deletions could be learned through cloning and Sanger sequencing ( Cai et al., 2018 ). Clinically, Sanger sequencing has been widely used to detect mutations such as BCR-ABL1 mutations associated with treatment resistance for a long time ( Deininger et al., 2016 ).…”

Section: Overview Of B Cell Receptor Repertoire Sequencing: Mainstrea...mentioning

confidence: 99%

B-cell receptor repertoire sequencing: Deeper digging into the mechanisms and clinical aspects of immune-mediated diseases

et al. 2022

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A rare e14a3 BCR/ABL fusion transcript in acute lymphoblastic leukemia patient treated with CAR-modified T-cell therapy

Cited by 5 publications

References 9 publications

Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3 Bcr-Abl1 Fusion Transcript: A Case Report

Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3 Bcr-Abl1 Fusion Transcript: A Case Report

Rapid decline of Philadelphia‑positive metaphases after nilotinib treatment in a cml patient expressing a rare e14a3 bcr‑abl1 fusion transcript: A case report

B-cell receptor repertoire sequencing: Deeper digging into the mechanisms and clinical aspects of immune-mediated diseases

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