Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response

Junichiro Yuda, Toshihiro Miyamoto, Jun Odawara, Yasuyuki Ohkawa, Yuichiro Semba, Masayasu Hayashi, Koichi Miyamura, Mitsune Tanimoto, Kazuhito Yamamoto, Masafumi Taniwaki, Koichi Akashi

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10 Citations (Scopus)


Treatment with tyrosine kinase inhibitors (TKI) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional PCR monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABLI ns35bp) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABLI ns35bp was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABLI ns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in the remaining all 34 patients, BCR-ABLI ns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR-ABLI ns35bp was persisted, although BCR-ABLI ns35bp does not definitively mark TKI resistance. Therefore, quantification of BCR-ABLI ns35bp is useful for evaluating “functional” MRD and determining the effectiveness of TKI with accuracy.

Original languageEnglish
Pages (from-to)2204-2212
Number of pages9
JournalCancer Science
Issue number11
Publication statusPublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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