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

TE RAA, G.D., P.D. MOERLAND, A.C. LEEKSMA, I.A. DERKS, H. YIGITTOP, N. LADDACH, M. LODEN-VAN STRAATEN, Veronika NAVRKALOVÁ, Martin TRBUŠEK, D.M. LUIJKS, T. ZENZ, A. SKOWRONSKA, M. HOOGENDOORN, T. STANKOVIC, M.H. VAN OERS, E. ELDERING and A.P. KATER. Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification. CELL DEATH & DISEASE. LONDON: NATURE PUBLISHING GROUP, 2015, vol. 6, august, p. "nestránkováno", 8 pp. ISSN 2041-4889. doi:10.1038/cddis.2015.223.

Basic information

• Original name: Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification
• Authors: TE RAA, G.D. (528 Netherlands), P.D. MOERLAND (528 Netherlands), A.C. LEEKSMA (528 Netherlands), I.A. DERKS (528 Netherlands), H. YIGITTOP (528 Netherlands), N. LADDACH (528 Netherlands), M. LODEN-VAN STRAATEN (528 Netherlands), Veronika NAVRKALOVÁ (203 Czech Republic, belonging to the institution), Martin TRBUŠEK (203 Czech Republic, guarantor, belonging to the institution), D.M. LUIJKS (528 Netherlands), T. ZENZ (276 Germany), A. SKOWRONSKA (826 United Kingdom of Great Britain and Northern Ireland), M. HOOGENDOORN (528 Netherlands), T. STANKOVIC (826 United Kingdom of Great Britain and Northern Ireland), M.H. VAN OERS (528 Netherlands), E. ELDERING (528 Netherlands) and A.P. KATER (528 Netherlands).
• Edition: CELL DEATH & DISEASE, LONDON, NATURE PUBLISHING GROUP, 2015, 2041-4889.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30200 3.2 Clinical medicine
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 5.378
• RIV identification code: RIV/00216224:14740/15:00085031
• Organization unit: Central European Institute of Technology
• Doi: http://dx.doi.org/10.1038/cddis.2015.223
• UT WoS: 000360581900016
• Keywords in English: TREATMENT-FREE SURVIVAL; TP53 MUTATION; DNA-DAMAGE; GENE; DYSFUNCTION; CLL; CELLS; INACTIVATION; DELETION; FLUDARABINE
• Tags: podil, rivok
• Tags: International impact, Reviewed

Abstract

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.