Characterization of ABL exon 7 deletion by molecular genetic and bioinformatic methods reveals no association with imatinib resistance in chronic myeloid leukemia

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6 Citations (Scopus)

Abstract

In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCRABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (Δexon7) was characterized in this study. The frequency of Δexon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The Δexon7 was abundantly detected with similar frequency in healthy controls, in imatinib naive and resistant CML patients on BCR-ABL and also on the nontranslocated ABL. The detection rate of Δexon7 (varying between 17 and 100%) was highly dependent on the expression levels of BCR-ABL or ABL and the sensitivity of detection method. According to secondary structure prediction by bioinformatic methods, the exon 7 deleted mRNA is a target for nonsense-mediated decay, and the translated protein is likely to be nonfunctional and unstable. Taken together all the above observations, we concluded that Δexon7 is a common splice variant not associating with imatinib resistance.

Original languageEnglish
Pages (from-to)2136-2142
Number of pages7
JournalMedical Oncology
Volume29
Issue number3
DOIs
Publication statusPublished - Sep 2012

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Computational Biology
Molecular Biology
Exons
Clonal Evolution
Alternative Splicing
Protein-Tyrosine Kinases
Imatinib Mesylate
Proteins
Alleles
Polymerase Chain Reaction
Messenger RNA
Mutation

Keywords

  • BCR-ABL
  • Bioinformatic prediction
  • CML
  • Exon 7 deletion
  • Imatinib resistance
  • Splice variant

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Hematology

Cite this

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title = "Characterization of ABL exon 7 deletion by molecular genetic and bioinformatic methods reveals no association with imatinib resistance in chronic myeloid leukemia",
abstract = "In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCRABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (Δexon7) was characterized in this study. The frequency of Δexon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The Δexon7 was abundantly detected with similar frequency in healthy controls, in imatinib naive and resistant CML patients on BCR-ABL and also on the nontranslocated ABL. The detection rate of Δexon7 (varying between 17 and 100{\%}) was highly dependent on the expression levels of BCR-ABL or ABL and the sensitivity of detection method. According to secondary structure prediction by bioinformatic methods, the exon 7 deleted mRNA is a target for nonsense-mediated decay, and the translated protein is likely to be nonfunctional and unstable. Taken together all the above observations, we concluded that Δexon7 is a common splice variant not associating with imatinib resistance.",
keywords = "BCR-ABL, Bioinformatic prediction, CML, Exon 7 deletion, Imatinib resistance, Splice variant",
author = "N{\'o}ra Meggyesi and Lajos Kalm{\'a}r and S{\'a}ndor Fekete and Tam{\'a}s Masszi and Attila Tordai and Hajnalka Andrikovics",
year = "2012",
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T1 - Characterization of ABL exon 7 deletion by molecular genetic and bioinformatic methods reveals no association with imatinib resistance in chronic myeloid leukemia

AU - Meggyesi, Nóra

AU - Kalmár, Lajos

AU - Fekete, Sándor

AU - Masszi, Tamás

AU - Tordai, Attila

AU - Andrikovics, Hajnalka

PY - 2012/9

Y1 - 2012/9

N2 - In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCRABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (Δexon7) was characterized in this study. The frequency of Δexon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The Δexon7 was abundantly detected with similar frequency in healthy controls, in imatinib naive and resistant CML patients on BCR-ABL and also on the nontranslocated ABL. The detection rate of Δexon7 (varying between 17 and 100%) was highly dependent on the expression levels of BCR-ABL or ABL and the sensitivity of detection method. According to secondary structure prediction by bioinformatic methods, the exon 7 deleted mRNA is a target for nonsense-mediated decay, and the translated protein is likely to be nonfunctional and unstable. Taken together all the above observations, we concluded that Δexon7 is a common splice variant not associating with imatinib resistance.

AB - In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCRABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (Δexon7) was characterized in this study. The frequency of Δexon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The Δexon7 was abundantly detected with similar frequency in healthy controls, in imatinib naive and resistant CML patients on BCR-ABL and also on the nontranslocated ABL. The detection rate of Δexon7 (varying between 17 and 100%) was highly dependent on the expression levels of BCR-ABL or ABL and the sensitivity of detection method. According to secondary structure prediction by bioinformatic methods, the exon 7 deleted mRNA is a target for nonsense-mediated decay, and the translated protein is likely to be nonfunctional and unstable. Taken together all the above observations, we concluded that Δexon7 is a common splice variant not associating with imatinib resistance.

KW - BCR-ABL

KW - Bioinformatic prediction

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KW - Exon 7 deletion

KW - Imatinib resistance

KW - Splice variant

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