Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

Stefano J. Mandriota, Linda J. Valentijn, Laurence Lesne, David R. Betts, Denis Marino, Mary Boudal-Khoshbeen, Wendy B. London, Anne Laure Rougemont, Edward F. Attiyeh, John M. Maris, Michael D. Hogarty, Jan Koster, Jan J. Molenaar, Rogier Versteeg, Marc Ansari, Fabienne Gumy-Pause

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

23 Citaten (Scopus)

Samenvatting

Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.

Originele taal-2Engels
Pagina's (van-tot)18558-18576
Aantal pagina's19
TijdschriftOncotarget
Volume6
Nummer van het tijdschrift21
DOI's
StatusGepubliceerd - 2015
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism'. Samen vormen ze een unieke vingerafdruk.

Citeer dit