Publication details

Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification

Authors

TE RAA G.D. MOERLAND P.D. LEEKSMA A.C. DERKS I.A. YIGITTOP H. LADDACH N. LODEN-VAN STRAATEN M. NAVRKALOVÁ Veronika TRBUŠEK Martin LUIJKS D.M. ZENZ T. SKOWRONSKA A. HOOGENDOORN M. STANKOVIC T. VAN OERS M.H. ELDERING E. KATER A.P.

Year of publication 2015
Type Article in Periodical
Magazine / Source CELL DEATH & DISEASE
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://www.nature.com/cddis/journal/v6/n8/pdf/cddis2015223a.pdf
Doi http://dx.doi.org/10.1038/cddis.2015.223
Field Oncology and hematology
Keywords TREATMENT-FREE SURVIVAL; TP53 MUTATION; DNA-DAMAGE; GENE; DYSFUNCTION; CLL; CELLS; INACTIVATION; DELETION; FLUDARABINE
Attached files
Description The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53-or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL.

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