ABL-kinase domain point mutation as a cause of imatinib (STI571) resistance in CML patient who progress to myeloid blast crisis

Sacha, Tomasz; Hochhaus, Andreas; Hanfstein, Benjamin; Müller, Martin C.; Rudzki, Zbigniew; Czopek, Jacek; Wolska-Smoleń, Teresa; Czekalska, Sylwia; Salamanchuk, Zoriana; Jakóbczyk, Małgorzata; Skotnicki, Aleksander B.

doi:10.1016/s0145-2126(03)00117-6

Cited by 15 publications

(11 citation statements)

References 6 publications

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“…Resistance against Imatinib in human patients is frequently associated with the outgrowth of a clone expressing a Bcr/Abl protein with point mutations in the ATP binding site, and T315 is the most frequently mutated residue in patients (25). To conclusively exclude the possibility that these cultures represented outgrowth of cells containing point mutations in the Abl ATP binding domain, we isolated DNA from V-7 and S-6, which were resistant to 5 Amol/L Imatinib.…”

Section: Resultsmentioning

confidence: 99%

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Resistance to Imatinib of Bcr/Abl P190 Lymphoblastic Leukemia Cells

et al. 2006

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Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 Amol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 Amol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinibresistant lymphoblasts did not require direct cell-cell contact. SDF-1a could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells. (Cancer Res 2006; 66(10): 5387-93)

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Section: Resultsmentioning

confidence: 99%

“…This region encompasses point mutations detected in human patients at amino acid residues T315, F317, M351, and H396 (i.e., refs. 24,25). We also sequenced a larger 675-bp region including both the ATP binding pocket and the activation loop using the primers and as described by Sacha et al (25).…”

Section: Methodsmentioning

confidence: 99%

Resistance to Imatinib of Bcr/Abl P190 Lymphoblastic Leukemia Cells

et al. 2006

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“…First round PCR is made with primer pairs to amplify fusion gene BCR-ABL1 and followed by second round PCR to amplify the kinase domain within the ABL gene to ensure the amplification of the right region. This protocol has been described by Sacha, 2003 and adapted by our lab (Figure 1) [15]. The PCR master mix used was KAPA HiFi HotStart ReadyMix (KAPA Biosystems, MA, USA).…”

Section: Bcr-abl1 Kinase Domain (Kd) Amplificationmentioning

confidence: 99%

Utilization of Next-Generation Deep Sequencing to Analyze BCR-ABL1 Kinase Domain Mutation for Imatinib-Resistant Chronic Myeloid Leukemia Patients in Vietnam

Cq¹,

Nguyen²,

Tt³

et al. 2017

J Leuk

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Background: Chronic myeloid leukemia is a clonal myeloproliferative neoplasm, characterized by the presence of chromosomal translocation t(9; 22)(q34; q11). This is found in over 95% of the cases and results in the BCR-ABL1 fusion protein with high tyrosine kinase activity. During the last decades, imatinib and other generations of tyrosine kinase inhibitor have been used effectively for target therapy of the disease. However, many of the drug resistant cases have been reported recently, due to the mutation within kinase domain of the BCR-ABL1 fusion gene. In order to provide further information about this incidence, we performed a retrospective study of 141 imatinib-resistance chronic myeloid leukemia patients to analyze kinase domain mutation by deep sequencing. Another group of 20 untreated patients were added as control.

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“…The ABL kinase domain of the BCR-ABL fusion gene was amplified using nested RT-PCR, followed by direct sequencing as described previously (Sacha et al, 2003). Briefly, the BCR-ABL allele was amplified using a forward primer that annealed to the BCR exon b2 and a reverse primer that annealed to the exon 7 of the ABL gene.…”

Section: Pcr Amplification and Mutation Analysismentioning

confidence: 99%