z-logo
open-access-imgOpen Access
Persistent detection of alternatively spliced BCR ‐ ABL variant results in a failure to achieve deep molecular response
Author(s) -
Yuda Junichiro,
Miyamoto Toshihiro,
Odawara Jun,
Ohkawa Yasuyuki,
Semba Yuichiro,
Hayashi Masayasu,
Miyamura Koichi,
Tanimoto Mitsune,
Yamamoto Kazuhito,
Taniwaki Masafumi,
Akashi Koichi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13353
Subject(s) - nilotinib , breakpoint cluster region , imatinib , tyrosine kinase , cancer research , myeloid leukemia , minimal residual disease , dasatinib , medicine , abl , biology , leukemia , immunology , receptor
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 ‐ ABL Ins35bp ) 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 ‐ ABL Ins35bp was detected in all patients. After switching to nilotinib, both BCR ‐ ABL and BCR ‐ ABL Ins35bp became undetectable in 3 patients who attained complete molecular response ( CMR ), whereas in the remaining all 34 patients, BCR ‐ ABL Ins35bp was persistently detected, and minimal residual disease ( MRD ) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR ‐ ABL Ins35bp was persisted, although BCR ‐ ABL Ins35bp does not definitively mark TKI resistance. Therefore, quantification of BCR ‐ ABL Ins35bp is useful for evaluating “functional” MRD and determining the effectiveness of TKI with accuracy.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here