An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy

Jennifer Laudadio, Michael W N Deininger, Michael J. Mauro, Brian Druker, Richard Press

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Although targeted inhibition of BCR-ABL with imatinib is an effective therapy for patients with chronic myeloid leukemia (CML), a minority of patients acquire mutations in the BCR-ABL kinase domain, resulting in imatinib resistance. The spectrum of kinase domain mutations discovered to date is quite heterogeneous, consisting almost exclusively of single nucleotide substitutions affecting key amino acids that regulate drug binding or BCR-ABL function. Here, we describe an alternative kinase domain insertion/truncation mutation in three CML patients undergoing kinase inhibitor therapy. In each of these patients, direct DNA sequencing of BCR-ABL RT-PCR products revealed that the same 35 nucleotides from ABL intron 8 had been inserted at the normal exon 8 to 9 splice junction. This 35-bp intronic sequence was flanked by excellent consensus splice donor and acceptor sequences, suggesting alternative splicing as the likely mutational mechanism. The insertion created a premature translational stop codon after 10 intron-encoded amino acids (amino acid 484). This resulted in truncation of 653 C-terminal amino acids, which included part of the kinase domain and the entire "last exon" region. These findings demonstrate that kinase domain insertions are an alternative (and not entirely uncommon) mutational mechanism in CML patients undergoing kinase inhibitor therapy.

Original languageEnglish (US)
Pages (from-to)177-180
Number of pages4
JournalJournal of Molecular Diagnostics
Volume10
Issue number2
DOIs
StatePublished - Mar 2008

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Insertional Mutagenesis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Introns
Phosphotransferases
Amino Acids
Therapeutics
Exons
Nucleotides
Mutation
Nonsense Codon
Alternative Splicing
DNA Sequence Analysis
Tissue Donors
Polymerase Chain Reaction
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology

Cite this

An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy. / Laudadio, Jennifer; Deininger, Michael W N; Mauro, Michael J.; Druker, Brian; Press, Richard.

In: Journal of Molecular Diagnostics, Vol. 10, No. 2, 03.2008, p. 177-180.

Research output: Contribution to journalArticle

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