Incidence and clinical importance of BCR-ABL1 mutations in Iranian patients with chronic myeloid leukemia on imatinib

Abstract

Mutations of the BCR-ABL1 kinase domain seem to be the most common cause of imatinib mesylate resistance in chronic myeloid leukemia (CML). We screened BCR-ABL1 kinase domain mutations using nested reverse transcriptase polymerase chain reaction and direct sequencing in 30 CML patients including 22 resistant patients and 8 patients with optimal response to imatinib. Three mutations of two different types were identified in 3 of 22 (13.6%) resistant patients. Two patients had p.E355G mutation in the catalytic domain, and the third patient had p.G398R in the activation loop that is reported here for the first time. No mutation was found in patients with optimal response to imatinib. The frequency of mutations was similar in patients with primary resistance compared with patients with secondary resistance (25 vs 11%; P=1). Mutation status had no impact on the overall survival and progression-free survival. p.E355G mutation was correlated with shorter survival (P=0.047) in resistant patients. We conclude that BCR- ABL1 mutations are associated with the clinical resistance, but may not be considered the only cause of resistance to imatinib. Mutational analysis may identify resistant patients at risk of disease progression.

The Frequency of BCR-ABL1 Fusion Transcripts in Iranian Patients with Three Different Types of Leukemia

“…It is also reported in 10% to 20% of adults and in 2% to 5% of children with acute lymphoblastic leukemia (ALL), and in very rarely cases of acute myeloid leukemia (AML) [1,3].…”

“…In approximately 60% of Philadelphia chromosome positive ALL patients and in some cases of CML and AML the BCR breakpoint falls within the minor breakpoint cluster region (mbcr ) that causes hybrid transcript containing an e1a2 junction, which is translated into a 190 kDa fusion protein (p190 BCR-ABL ) [4,5]. In the remaining Ph positive ALL patients (40%), the breakpoint occurs in the Mbcr region [1,6]. The micro breakpoint cluster region (µ-bcr) between BCR exon 19 and 20, result in the joining of exon 19 (e19) of bcr with a2, e19a2, coding for a 230-kDa (p230) protein has been report in rare cases of CML [7].…”

“…In the majority of CML patients (95%) the breakpoint in the BCR gene falls within the major breakpoint cluster region (Mbcr), and the resultant BCR-ABL mRNA molecules with a b2a2 (40%) or b3a2 (55%) junction encode a 210 kDa fusion protein (p210 BCR-ABL ) [1]. In 5% of CML patients, both b3a2 and b2a2 transcripts can be made as a result of alternative splicing [1,3].…”

“…In 5% of CML patients, both b3a2 and b2a2 transcripts can be made as a result of alternative splicing [1,3]. In approximately 60% of Philadelphia chromosome positive ALL patients and in some cases of CML and AML the BCR breakpoint falls within the minor breakpoint cluster region (mbcr ) that causes hybrid transcript containing an e1a2 junction, which is translated into a 190 kDa fusion protein (p190 BCR-ABL ) [4,5].…”

“…This translocation causes the formation of BCR-ABL fusion gene, and is associated often with chronic myeloid leukemia (CML) [1]. More than 95% of patients with CML are positive for a BCR-ABL gene in their leukemia cells [2].…”