valine and epigallocatechin was detected in a chronic phase CML patient who did not achieve complete cytogenetic response after 32 months of imatinib therapy and was switched to nilotinib for about 10 months. The third type was a deletion of a single nucleotide, resulting in a frameshift mutation of 27 amino acids, which was located outside the KD and was detected in a young chronic phase CML patient who had a primary imatinib resistance and a variant Philadelphia Silodosin clinical trial chromosome . In this study, the KD mutations were mainly clustered in the SH3 contact and C helix domain in the nave cases. On the other hand, most of the mutations in the TKI exposed cases were localized in the drug contact site, P loop, and catalytic domain with the most frequent mutation being T315I. The insensitive type of mutation was also found in nave cases such as E255V.
However, the most resistant mutation, i.e. T315I could not be detected in any of the 80 nave CML Nilotinib structure cases in this series. A high incidence of T315I was noted in cases with exposure to both imatinib and secondgeneration TKI and cases with advanced phase who received second generation TKI only, suggesting that T315I is strongly associated with TKI exposure and/or advanced phase of the disease. Kim et al. showed that T315I preferentially occurred in the Korean patients with advanced phase as contrasted to chronic phase, suggesting that the frequency of resistant mutation increased as the disease progressed. The fact that we found naturally occurring mutations in the nave cases was consistent with most previous small reports.
We are, however, intrigued by the fact that T315I could not be demonstrated in Gefitinib solubility any of our nave cases, some of whom were also exposed to conventional chemotherapy. Our study was in agreement with Carella et al. who did not find T315I in a nave cohort from Italy. E255V and C330G without T315I were also reported in a small nave cohort receiving hydroxyurea from India. Contradictory results came from Roche Lestienne et al. who found resistant mutations such as T315I and F311L in a cohort of 24 TKI unexposed CML cases from France. T315I, Y253F/H, Q252H, M351T, M244V, and F359V had also been reported in TKIunexposed cases from Germany who had a history of hydroxyurea, interferon, and cytarabine treatment.
The fact that our nave case had a milder resistant mutation such as E255V but lack T315I and nationalism M351T could indicate the differential occurrence of types of mutations at various stages of disease that were precipitated by different types of TKI exposure. Conclusion Thirteen known and 8 novel mutations were identified in this study. Various types of sensitive and resistant mutations exist in the leukemic cells with no previous TKI exposure and the mutation frequency appears to increase with TKI exposure. T315I was potentially induced to arise by first and second generation TKI drugs as it could not be found in any of our nave Southeast Asian cases. Larger clinical studies should be performed to delineate the impact of the known and novel mutations identified in this population. Alternative mechanisms to explain TKI resistance should also be entertained if KD mutations were not detected such as mutations outside the KD in the neighboring regions, clonal chromosomal evolution, BCR ABL amplification, and