The p53 pathway induction is not primarily dependent on Ataxia Telangiectasia Mutated (ATM) gene activity after fludarabine treatment in chronic lymphocytic leukemia cells
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Transcriptional Activation * MeSH
- Ataxia Telangiectasia Mutated Proteins genetics metabolism MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell drug therapy genetics metabolism MeSH
- DNA Breaks, Double-Stranded MeSH
- Histones genetics MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 metabolism MeSH
- Proliferating Cell Nuclear Antigen metabolism MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Gene Expression Regulation, Leukemic drug effects MeSH
- Signal Transduction * MeSH
- Vidarabine analogs & derivatives pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Ataxia Telangiectasia Mutated Proteins MeSH
- fludarabine MeSH Browser
- H2AX protein, human MeSH Browser
- Histones MeSH
- Tumor Suppressor Protein p53 MeSH
- Proliferating Cell Nuclear Antigen MeSH
- Antineoplastic Agents MeSH
- Vidarabine MeSH
The prognostic role of ATM defects is well documented in chronic lymphocytic leukemia. However, the predictive value of ATM inactivation is much less understood, even in response to common drugs like fludarabine. It has been demonstrated that CLL cells having inactive ATM exhibit defective phosphorylation of its downstream targets after fludarabine treatment. We performed alternative analysis focusing on fludarabine-induced p53 accumulation and induction of p53-downstream genes after artificial ATM inhibition and, in parallel, using cells with endogenous ATM inactivation. We show that after 24h fludarabine exposure: (i) 5 out of 8 ATM-deficient samples (63%) normally accumulated p53 protein, and (ii) all analyzed ATM-deficient samples (n = 7) manifested clear induction of p21, PUMA, BAX, and GADD45 genes. In all experiments, doxorubicin was used as a confined ATM inductor and confirmed effective ATM inactivation. In conclusion, CLL cells lacking functional ATM appear to have normal response to fludarabine regarding the p53 pathway activation.
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