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

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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	ZVV_2015_150_1319554_Assesment_of_p53.pdf
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.