MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations
| Autor: | Soon Keng Cheong, A Simbun, Nor Rafeah Tumian, E Yap, Chooi Fun Leong, Zainul Abidin Norziha, Chieh Lee Wong |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Cancer Research DNA Repair Fusion Proteins bcr-abl Down-Regulation Biology 03 medical and health sciences 0302 clinical medicine Fanconi anemia hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive microRNA Gene expression medicine Humans Computer Simulation Gene BRCA1 Protein Myeloid leukemia Hematology Middle Aged medicine.disease FANCA MicroRNAs 030104 developmental biology Imatinib mesylate Fanconi Anemia Oncology Gene Expression Regulation Drug Resistance Neoplasm 030220 oncology & carcinogenesis Case-Control Studies Immunology Cancer research Imatinib Mesylate RAD51C |
| Zdroj: | Leukemia research. 59 |
| ISSN: | 1873-5835 |
| Popis: | Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets. |
| Databáze: | OpenAIRE |
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