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Introduction
Chronic myeloid leukemia (CML), a hematopoietic malignancy, is characterized by the formation of the Philadelphia chromosome (Ph), which arises via a reciprocal translocation between chromosomes 9 and 22 (Kurzrock et al., 1988). The bcr-abl fusion oncogene generated at the break point encodes a constitutively active tyrosine kinase (Kurzrock et al., 1998) and acts as a causative driver gene in CML through the tyrosine phosphorylation of its substrates, including CrkL and signal transducer and activator of transcription (Groffen et al., 1984; Heisterkamp et al., 1982). In 2001, the tyrosine kinase inhibitor imatinib mesylate (IM) was approved as a first-line therapy for CML (Druker, 2008; Druker et al., 1996). The therapeutic outcomes associated with this agent are better than those of alternative options, which include chemotherapy, interferon, and allogeneic hematopoietic stem cell transplantation. This means that CML is a disease that can be effectively controlled by oral medication (Druker, 2008; Druker et al., 1996).
Although the overall 5-year survival rate of IM-treated patients is approximately 80%, a considerable number of patients do not demonstrate optimal responses to this therapy. In addition, IM resistance is acquired during treatment in certain cases. Resistance is attributable to mutations in the Abl kinase domain in ~50% of cases. In this situation, the second-generation drugs nilotinib (NL) and dasatinib (DS) are available, and their effectiveness is predictable based on the types of mutations present (Weisberg et al., 2007). However, if no mutations are detected, because of either a lack of mutation or the presence of a small population of mutation-positive cells, drug efficacy is determined through the long-term follow-up of alterations in disease status, as determined by blood and bone marrow tests (throughout the treatment period, and then for several months to a year or more). Clinical tests include total blood cell count, detection of Ph by fluorescence in-situ hybridization, and quantification of BCR-ABL mRNA levels by qPCR (Kantarjian et al., 2002; Preudhomme et al., 1999; Tkachuk et al., 1990). Although BCR-ABL mRNA quantification is widely used to monitor disease status and drug efficacy, it reflects the number of tumor cells present and hence only measures current drug treatment outcomes. Therefore, the development of techniques to predict future responsiveness is desirable.