INTRODUCTION: Multiple types of mutations in the BCR-ABL1 kinase domain have been reported. We previously reported a common alternatively spliced BCR-ABL mRNA with a 35-nucleotide insertion (35INS). We report three novel alternative splicing mutants expressed as the dominant transcripts in patient with chronic myelogenous leukemia and resistance to kinase inhibitors. METHODS: We screened RNA from more than 200 patients with resistance to more than one of the three kinase inhibitors for ABL1 kinase domain mutations by direct sequencing. RESULTS: We found three not previously described splice mutants. All three showed >90% mutant transcript. The first resulted from the insertion of 79 nucleotides into the ABL1 exon 8-9 junction. The inserted sequence contained a sequence from regions of intron 8, located 120 bp apart: the 35-nucleotide sequence previously described, and an additional 44-nucleotide segment downstream from 35INS. The combined 79-nucleotide insertion splice mutant showed the same protein change as 35INS (p C475YfsX11). The second splice mutation comprised an 84-nucleotide sequence from intron 7 inserted into the ABL1 exon7-8 junction, also causing a frameshift and protein truncation (p A424EfsX18). The third splice derived from a 231-nucleotide sequence from intron 4 retained in the ABL1 exon 4-5 junction adding 40 intron-encoded amino acids and leading to a frameshift and early termination (p E275LfsX41). CONCLUSION: These findings, when combined with the data on 35INS, support the concept that loss of the C-terminus of BCR-ABL1 is associated with significant resistance to kinase inhibitors; this mechanism appears to be a major source of resistance to kinase inhibitors.
INTRODUCTION: Multiple types of mutations in the BCR-ABL1 kinase domain have been reported. We previously reported a common alternatively spliced BCR-ABL mRNA with a 35-nucleotide insertion (35INS). We report three novel alternative splicing mutants expressed as the dominant transcripts in patient with chronic myelogenous leukemia and resistance to kinase inhibitors. METHODS: We screened RNA from more than 200 patients with resistance to more than one of the three kinase inhibitors for ABL1 kinase domain mutations by direct sequencing. RESULTS: We found three not previously described splice mutants. All three showed >90% mutant transcript. The first resulted from the insertion of 79 nucleotides into the ABL1 exon 8-9 junction. The inserted sequence contained a sequence from regions of intron 8, located 120 bp apart: the 35-nucleotide sequence previously described, and an additional 44-nucleotide segment downstream from 35INS. The combined 79-nucleotide insertion splice mutant showed the same protein change as 35INS (p C475YfsX11). The second splice mutation comprised an 84-nucleotide sequence from intron 7 inserted into the ABL1 exon7-8 junction, also causing a frameshift and protein truncation (p A424EfsX18). The third splice derived from a 231-nucleotide sequence from intron 4 retained in the ABL1 exon 4-5 junction adding 40 intron-encoded amino acids and leading to a frameshift and early termination (p E275LfsX41). CONCLUSION: These findings, when combined with the data on 35INS, support the concept that loss of the C-terminus of BCR-ABL1 is associated with significant resistance to kinase inhibitors; this mechanism appears to be a major source of resistance to kinase inhibitors.
Authors: Nóra Meggyesi; Lajos Kalmár; Sándor Fekete; Tamás Masszi; Attila Tordai; Hajnalka Andrikovics Journal: Med Oncol Date: 2011-10-30 Impact factor: 3.064
Authors: Ulf Schmitz; Jaynish S Shah; Bijay P Dhungel; Geoffray Monteuuis; Phuc-Loi Luu; Veronika Petrova; Cynthia Metierre; Shalima S Nair; Charles G Bailey; Verity A Saunders; Ali G Turhan; Deborah L White; Susan Branford; Susan J Clark; Timothy P Hughes; Justin J-L Wong; John E J Rasko Journal: Cancers (Basel) Date: 2020-12-11 Impact factor: 6.639