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ABL single nucleotide polymorphisms may masquerade as BCR-ABL mutations associated with resistance to tyrosine kinase inhibitors in CML patients

III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

Correspondence: Thomas Ernst, III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany. E-mail:thomas.ernst{at}med3.ma.uni-heidelberg.de

ABSTRACT

The BCR-ABL K247R change is based on a rare single nucleotide polymorphism (SNP) occurring likewise in healthy controls and non-hematologic cell types. Despite its juxtaposition to the P-loop, functional analysis showed no alteration compared to non-mutated BCR-ABL. We sought to investigate if other changes in the BCR-ABL kinase domain should be considered as SNPs rather than acquired mutations. A total of 911 CML patients after failure or suboptimal response to imatinib were screened for BCR-ABL kinase domain mutations. SNP analysis was based on the search for nucleotide changes in corresponding normal, non-translocated ABL alleles by ABL allele-specific PCR following mutation analysis. In addition to the K247R polymorphism we uncovered five new SNPs within the BCR-ABL kinase domain; two of them led to amino acid changes. SNPs could theoretically contribute to primary but not to secondary resistance to tyrosine kinase inhibitors and must therefore be distinguished from acquired mutations. Novel point mutations should be confirmed by analyzing the normal ABL alleles to exclude polymorphisms.

Key words: SNP, polymorphism, BCR-ABL mutation, imatinib resistance, CML.