Two different point mutations in ABL gene ATP-binding domain conferring primary imatinib resistance in a chronic myeloid leukemia (CML) patient: A case report

Abstract

Imatinib (Gleevec) is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO) PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance.

Molecular Screening for E255K and F359V Mutations in Non-Responders Iraqi Chronic Myeloid Leukemia Patients to Imatinib Mesylate Therapy

“…Point mutations result in substitution of Glutamine (E) to Lysine (K) at position 255 and Phenyl alanine (F) to Valine (V) at position 359 of BCR-ABL tyrosine kinase were screened by ASO-PCR (Iqbal, Siddiqui, & Qureshi, 2004). Patient´s DNA and DNA from healthy individuals were amplified by using ASO-primers as well as internal control-primers in separate reaction mixtures.…”

Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase signaling: Current patterns of the versatile regulator revisited

“…[7] In contrast, a cytosine-to-thymine mutation at ABL1 gene position 944 was identified, which takes part in threonine-to-isoleucine amino acid substitution at amino acid position 315 in ATP-binding domain of BCR-ABL1oncoprotein. [8][9][10] It has been dogged, on the basis of the crystal structure of ABL1 kinase domain, that Threonine 315 is among those amino acids which make hydrogen bonds with Gleevec by providing an oxygen atom. Moreover, it holds an extra hydrocarbon group in the side chain, which fallouts in steric hindrance to Gleevec.…”

“…The restless transgenic activity of mutated BCR-ABL1, resistant to imatinib, includes a vital role in the CML progression. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Recently it has been reported that rapamycin-treated CML cell line (K562) highlighted a decreased mTOR, 4E-BP1, and p70S6K phosphorylation. Treatment with higher dose (20nmol/l or more) of rapamycin increases apoptotic cells, decreases bcl-2 expression, and activates caspase-3.…”

Advances in the treatment of haematological malignancies: optimal sequence of CML treatment

“…The development of highly sensitive, PCR-based screening assays has greatly facilitated the detection and identification of point mutations in imatinib-resistant patients, and could be useful for prediction of the most ideal course of treatment for these patients as well as patients resistant to the second generation BCR-ABL inhibitors [18,[27][28][29]. The highly sensitive allele-specific-oligonucleotide PCR method was used for detection of the first set of BCR-ABL point mutations shown to simultaneously exist in an imatinib-resistant CML patient.…”