The known mutations in our nave patients, E255V, E279K, and L273L, were VX-950 also discovered at a low level in newly diagnose CML patients as reported by Soverini et al. and Press et al. The known mutant V304A in our imatinib response patient, have been discovered in CD34 cells from imatinib treated CML patients by Chu et al. and Jiang et al. and they also indicated that V304 have been associated with imatinib resistance in patient. Recently, Jones et al. described V304A in imatinibtreated patient and underwent absence after switch to a new TKI with major molecular response. Among the Chinese cases, the most frequent mutation was M244V followed by Y253H, F359C/V/I, G250E, E255K, T315I, and M351V whereas the most frequent mutation in the Indian and Korean series was T315I.
T315I was also the most frequent mutation in our Thai cohort followed by Y253H, M251T, and G250E, but M244V which was common in the Chinese and Indian cohorts was only found in 1 case in this study. In addition, M351T was also noted to be uncommon in imatinib resistant CML patients from Asia. The variations Rapamycin clinical trial in the KD mutation frequency and types may reflect geographic heterogeneity among various ethnic populations. Eight different types of novel mutations were found among nave and exposed cases. They were clustered in 3 regions: 3 located within exon 4, 3 located in exon 5, 1 located within exon 6, and one within exon 7. Based on the Polyphen website, these novel point mutations could be categorized into 3 groups, i.e.
1 the variants were predicted to be probably damaging and might be a mutation, 2 the variants werepredicted Sunitinib structure to be benign, which might be a SNP, and 3 the silent mutation, which may not have any effect on the ABL KD protein structure and function. Among the nave cases, the first type of mutation was a deletion of 32 nucleotides, leading to a novel frameshift mutation and premature stop codon resulting in a truncated BCR ABL protein. This type of deletion was found in a chronic phase CML patient who had been on hydroxyurea for 12 year and had never been treated with imatinib. The second type of mutation was a T to A substitution at codon 301 causing the change of leucine to histidine. L301H was found in a chronic phase CML patient who also had another known mutation, E255V.
The third type of mutation was a single nucleotide duplication within codon 311 resulting in a frameshift mutation Irbesartan solubility of 6 amino acids unity which occurred within the drug binding domain. The fourth type of mutation was a silent mutation, H295H, which was found in an acceleratedphase CML patient who had been on hydroxyurea for 12 months. The fifth type of mutation was a silent mutation as described above was found the homozygous mutants peak, GA substitution.There were three novel mutations in exposed cases, the first of which was identified as H246Y which was a C to T substitution at codon 246, causing the change of histidine to tyrosine. H246Y was found in a chronic phase CML patient who developed imatinib intolerance after a 30 month therapy. The same amino acid position with a different amino acid type to H246H, E258D, had been reported in a previous study by Ernst et al. The second mutation was a C to T substitution at codon .