ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin
| Autor: | Martin Trbušek, Jana Kminkova, Yvona Brychtová, Marek Mráz, Ludmila Šebejová, Veronika Navrkalová, Šárka Pospíšilová, Jitka Malčíková, Blanka Kubešová, Michael Doubek, Jiri Mayer, Jana Šmardová, Veronika Némethová, Jana Zemanová, David Potesil, Šárka Pavlová |
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| Jazyk: | angličtina |
| Předmět: |
Adult
Male Microarray Cell Survival Chronic lymphocytic leukemia Ataxia Telangiectasia Mutated Proteins Biology medicine.disease_cause Cohort Studies 03 medical and health sciences 0302 clinical medicine medicine Humans Doxorubicin Mutation frequency 030304 developmental biology Aged Retrospective Studies Aged 80 and over 0303 health sciences Mutation Chromosomes Human Pair 11 Hematology Middle Aged medicine.disease Molecular biology Leukemia Lymphocytic Chronic B-Cell 3. Good health Fludarabine Leukemia 030220 oncology & carcinogenesis Leukocytes Mononuclear Female Chromosome Deletion Original Articles and Brief Reports medicine.drug |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2012.081620 |
| Popis: | ATM abnormalities are frequent in chronic lymphocytic leukemia and represent an important prognostic factor. Sole 11q deletion does not result in ATM inactivation by contrast to biallelic defects involving mutations. Therefore, the analysis of ATM mutations and their functional impact is crucial. In this study, we analyzed ATM mutations in predominantly high-risk patients using: i) resequencing microarray and direct sequencing; ii) Western blot for total ATM level; iii) functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired p21 induction after doxorubicin exposure. We detected ATM mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired p21 upregulation after doxorubicin and/or null protein level). Loss of ATM function in mutated samples was also evidenced through defective p53 pathway activation after ionizing radiation exposure. ATM mutation frequency was 34% in patients with 11q deletion, 4% in the TP53-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for ATM mutations prediction. Only cells with ATM mutation, but not those with sole 11q deletion, were resistant to doxorubicin. As far as fludarabine is concerned, this difference was not observed. Interestingly, patients from both these groups experienced nearly identical time to first treatment. In conclusion, ATM mutations either alone or in combination with 11q deletion uniformly led to demonstrable ATM dysfunction in patients with chronic lymphocytic leukemia and mutation presence can be predicted by the functional test using doxorubicin. |
| Databáze: | OpenAIRE |
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