Detection of BCR-ABL1 Kinase Domain Mutations Causing Imatinib Resistance in Chronic Myelogenous Leukemia

2013 ◽  
pp. 25-39 ◽  
Author(s):  
Franklin R. Moore ◽  
Fei Yang ◽  
Richard D. Press
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Kinase Domain Mutations

Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4611-4614 ◽  
Author(s):  
Amie S. Corbin ◽  
Paul La Rosée ◽  
Eric P. Stoffregen ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Kinase ◽  
Cellular Assays ◽  
Kinase Domain Mutations

Abstract Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance.While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2128-2137 ◽  
Author(s):  
Stephanie G. Willis ◽  
Thoralf Lange ◽  
Shadmehr Demehri ◽  
Sandra Otto ◽  
Lucy Crossman ◽  
...  
Keyword(s):  
High Sensitivity ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Response To Therapy ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Allele Specific ◽  
Drug Resistant Phenotype ◽  
Kinase Domain Mutations ◽  
Cytogenetic Evolution

Abstract Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pretherapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinibnaive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 patients with chronic myelogenous leukemia (CML), using cDNA sequencing and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing, and 1 by sequencing only (overall frequency, 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 patients with positive ASO-PCR had follow-up samples available for sequencing. Wild-type sequence was detected in 6 of 11, 2 different mutations in 1 of 11, and identical mutations in 4 of 11 patients, 2 of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine, and a low platelet count, but not with response to imatinib, event-free survival, and overall survival. KD mutants present at low levels do not invariably lead to relapse, and additional factors are required to induce a fully drug-resistant phenotype. (Blood. 2005; 106:2128-2137)

scholarly journals Rapid Sequential Gain of ABL1 Kinase Domain Mutations with a Complex Karyotype in the Progression of Chronic Myelogenous Leukemia

2014 ◽  
Vol 34 (5) ◽  
pp. 399-401
Author(s):  
Yousun Chung ◽  
Hyeon-Seok Eom ◽  
Hyewon Lee ◽  
Sunseob Park ◽  
Hyoeun Shim ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Complex Karyotype ◽  
Kinase Domain Mutations

scholarly journals Predictors of Primary Imatinib Resistance in Chronic Myelogenous Leukemia Are Distinct From Those in Secondary Imatinib Resistance

2009 ◽  
Vol 27 (22) ◽  
pp. 3642-3649 ◽  
Author(s):  
Wenyong W. Zhang ◽  
Jorge E. Cortes ◽  
Hui Yao ◽  
Li Zhang ◽  
Neelima G. Reddy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Kinase Domain Mutations

Purpose A subset of patients with chronic myelogenous leukemia (CML) do not respond to the tyrosine kinase inhibitor (TKI) imatinib mesylate. Such primary imatinib resistance is distinguished from secondary resistance which reemerges after attainment of cytogenetic remission. Patients and Methods We studied gene expression patterns in total WBCs using a panel of 21 genes previously implicated in TKI handling, resistance, or progression comparing patients who had newly diagnosed TKI-naive CML that had optimal (n = 41), or suboptimal (n = 7) responses to imatinib, or primary resistance (n = 20). Expression patterns were compared to those in secondary TKI-resistant chronic phase CML without ABL1 kinase domain mutations (n = 29), and to lymphoid (n = 15) or myeloid blast phase disease (n = 12). Results Fifteen genes in the panel distinguished blast phase from chronic phase disease, and 12 genes distinguished newly diagnosed CML from TKI-resistant CML without ABL1 kinase domain mutations, but only a single gene, prostaglandin-endoperoxide synthase 1/cyclooxgenase 1 (PTGS1/COX1; P = .005), differentiated imatinib-responsive from primary imatinib-resistant CML. The association of primary imatinib resistance with higher transcript levels of the drug metabolism gene PTGS1 was confirmed in a separate data set of 68 newly diagnosed, imatinib-treated CML (P = .008). In contrast, up to 11 different genes were identified in a multivariate model that optimally discriminated secondary imatinib resistance lacking ABL1 kinase domain mutation from imatinib-responsive cases, likely related to the more complex pathogenesis of secondary resistance. Conclusion Gene expression profiling of CML at diagnosis for PTGS1 may be useful in predicting imatinib response and in selecting alternate therapy.

scholarly journals Imatinib resistance in a novel translocation der(17)t(1;17)(q25;p13) with loss of TP53 but without BCR/ABL kinase domain mutation in chronic myelogenous leukemia

2008 ◽  
Vol 183 (1) ◽  
pp. 77-81 ◽  
Author(s):  
Katsuya Yamamoto ◽  
Kimikazu Yakushijin ◽  
Shinichiro Nishikawa ◽  
Kentaro Minagawa ◽  
Yoshio Katayama ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Kinase ◽  
Kinase Domain Mutation
Sign in / Sign up

Export Citation Format

Share Document