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Published on: March 26, 2018
Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients
1III. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Universitätsklinikum Mannheim der Ruprecht-Karls-Universität Heidelberg, Mannheim, Germany. oliver.frank@med3.ma.uni-heidelberg.de
Abstract:
Although the selective tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia (CML), inherent mechanisms confer primary resistance to leukemic patients. In order to search for potentially useful genes in predicting cytogenetic response, a retrospective gene expression study was performed. Leukocyte RNA isolated before imatinib from interferon-alpha-pretreated chronic phase CML patients (n=34) with or without major cytogenetic remission (< or =35% Philadelphia (Ph)+ metaphases) during the first year of treatment was comparatively analyzed using Affymetrix U133A chips. Using support vector machines for gene classification, an outcome-specific gene expression signature consisting of 128 genes was identified. Comparative expression data of specific genes point to changes in apoptosis (e.g. casp9, tumor necrosis factor receptor-associated protein 1, hras), DNA repair (msh3, ddb2), oxidative stress protection (glutathione synthetase, paraoxonase 2, vanin 1) and centrosomes (inhibitor of differentiation-1) within primary resistant patients. Independent statistical approaches and quantitative real-time reverse transcriptase-polymerase chain reaction studies support the clinical relevance of gene profiling. In conclusion, this study establishes a candidate predictor of imatinib resistance in interferon-alpha-pretreated CML patients to be subjected to future investigation in a larger independent patient cohort. The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance.
Insights
This study identified a 128-gene signature predicting imatinib resistance in chronic myeloid leukemia (CML) patients. This gene profile may reveal BCR-ABL-independent resistance mechanisms, aiding future treatment strategies.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Imatinib is a tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML).
- Primary resistance to imatinib occurs in some CML patients due to inherent mechanisms.
- Predicting treatment response is crucial for optimizing CML therapy.
Purpose of the Study:
- To identify genes that predict cytogenetic response to imatinib in CML.
- To discover a gene expression signature associated with imatinib resistance.
- To explore potential BCR-ABL-independent mechanisms of resistance.
Main Methods:
- Retrospective gene expression analysis of leukocyte RNA from 34 interferon-alpha-pretreated CML patients.
- Utilized Affymetrix U133A chips for gene expression profiling.
- Applied support vector machines for gene classification and identified a 128-gene signature.
Main Results:
- A 128-gene expression signature was identified, differentiating patients with and without cytogenetic remission.
- Specific genes related to apoptosis, DNA repair, oxidative stress, and centrosomes were altered in resistant patients.
- Gene profiling results were validated using independent statistical approaches and quantitative real-time PCR.
Conclusions:
- A candidate gene expression signature may predict imatinib resistance in interferon-alpha-pretreated CML patients.
- The identified signature suggests the involvement of BCR-ABL-independent mechanisms in imatinib resistance.
- Further investigation in larger cohorts is warranted to validate these findings for clinical application.
