@article{Veronika Navrkalova_Ludmila Sebejova_Jana Zemanova_Jana Kminkova_Blanka Kubesova_Jitka Malcikova_Marek Mraz_Jana Smardova_Sarka Pavlova_Michael Doubek_Yvona Brychtova_David Potesil_Veronika Nemethova_Jiri Mayer_Sarka Pospisilova_Martin Trbusek_2013, place={Pavia, Italy}, title={ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin}, volume={98}, url={https://haematologica.org/article/view/6723}, DOI={10.3324/haematol.2012.081620}, abstractNote={<em>ATM</em> 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 <em>ATM</em> mutations and their functional impact is crucial. In this study, we analyzed <em>ATM</em> 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 <em>p21</em> gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired <em>p21</em> induction after doxorubicin exposure. We detected <em>ATM</em> mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired <em>p21</em> 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. <em>ATM</em> mutation frequency was 34% in patients with 11q deletion, 4% in the <em>TP53</em>-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for <em>ATM</em> mutations prediction. Only cells with <em>ATM</em> 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, <em>ATM</em&gt; 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.}, number={7}, journal={Haematologica}, author={Veronika Navrkalova and Ludmila Sebejova and Jana Zemanova and Jana Kminkova and Blanka Kubesova and Jitka Malcikova and Marek Mraz and Jana Smardova and Sarka Pavlova and Michael Doubek and Yvona Brychtova and David Potesil and Veronika Nemethova and Jiri Mayer and Sarka Pospisilova and Martin Trbusek}, year={2013}, month={Jun.}, pages={1124-1131} }