Abstract
Neuroblastoma (NB) is the most common extracranial childhood tumor classified in five stages (1, 2, 3, 4 and 4S), two of which (3 and 4) identify chemotherapy-resistant, highly aggressive disease. High-risk NB frequently displays MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in TERT genes. These NB subtypes are also characterized by reduced susceptibility to programmed cell death induced by chemotherapeutic drugs. The latter feature is a major cause of failure in the treatment of advanced NB patients. Thus, proper reactivation of apoptosis or of other types of programmed cell death pathways in response to treatment is relevant for the clinical management of aggressive forms of NB. In this short review, we will discuss the most relevant genomic rearrangements that define high-risk NB and the role that destabilization of p53 and p73 can have in NB aggressiveness. In addition, we will propose a strategy to stabilize p53 and p73 by using specific inhibitors of their ubiquitin-dependent degradation. Finally, we will introduce necroptosis as an alternative strategy to kill NB cells and increase tumor immunogenicity.
Highlights
MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in telomerase reverse transcriptase (TERT) genes are frequent in high-risk NB
MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in TERT genes are frequent in high-risk NB
One of the first and doubtlessly most important genetic signature of NB is the amplification of the proto-oncogene MYCN.[4,5,6]
Summary
Are there ongoing clinical trials that exploit specific apoptosis and/or necroptosis defects in NB?. A real breakthrough in the search for genomic alterations that impact on NB aggressiveness comes from the recent observation of telomerase reverse transcriptase (TERT) activation by genetic rearrangements in high-risk NB.[20] By whole-genomic sequencing of 59 NB cases the authors discovered recurrent genetic rearrangements in the chromosomal region 5p15.33 proximal of TERT. Rearrangements of this region took place only in high-risk NB (12 out of 39 = 31%). To p63, p73 is expressed as several distinct protein
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