Down‐regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation

Abstract

The tumour component of classical Hodgkin's lymphoma (cHL), Hodgkin Reed-Sternberg (HRS) cells, are believed to be derived from germinal centre (GC) B cells but intriguingly display a characteristic loss of B cell receptor (BCR) expression. The precise mechanisms by which BCR-negative HRS cell progenitors survive negative selection during the GC reaction remain obscure. Individuals with ataxia telangiectasia, caused by biallelic inactivation of the DNA damage response gene, ataxia telangiectasia mutated (ATM), have a higher risk of cHL development. Here we show that, in contrast to normal GC B cells that expressed low but detectable ATM protein, ATM protein was not detected in HRS cells of 17/18 cases of paediatric cHL, all but one with nodular sclerosis (NS) subtype. A comprehensive analysis of the ATM gene in microdissected HRS cells of nine representative tumours showed no evidence of either loss of heterozygosity or consistent pathogenic mutations. Furthermore, bisulphite sequencing of the ATM promoter from HRS cells of five tumours also revealed the absence of hypermethylation. Since our microarray data suggested significantly reduced ATM transcription in HRS cells compared to GC B cells, we conclude that loss of ATM expression could be the result of alterations in upstream regulators of ATM transcription. Importantly, ATM loss in paediatric cHLs has clinical implications and could be potentially exploited to guide future, less toxic, tumour-specific treatments.

Three Epstein–Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints

“…Our finding that LMP-1 inhibits ATM expression is in line with the reported loss of Genomic instability in EBV-infected cells B Gruhne et al ATM in EBV-carrying tumors that express latency II such as NPC and HD (Bose et al, 2009). Interestingly, downregulation of ATM was shown to occur in HD independently of EBV carriage (Bose et al, 2007), suggesting that it may constitute a critical event in pathogenesis. The possibility that different modes of regulation may prevail depending on LMP-1 expression was not explored.…”

A putative “hepitype” in the ATM gene associated with chronic lymphocytic leukemia risk

“…However, we found no evidence of ATM promoter hypermethylation in any of the analyzed samples. These data corroborate previous studies suggesting that epigenetic silencing of ATM by promoter hypermethylation is a rare event in the majority of lymphomas (Chim et al, 2005;Gumy-Pause et al, 2006;Bose et al, 2007).…”

Having Pancreatic Cancer with Tumoral Loss of ATM and Normal TP53 Protein Expression Is Associated with a Poorer Prognosis

“…This low prevalence of germline ATM mutations even in patients with familial pancreatic cancer likely means that the tumoral loss of ATM in both familial and sporadic pancreatic cancers arises in most cases as a somatic event. Somatic ATM inactivation is generally by intragenic mutation according to the literature, although other mechanisms are possible (23). Recent studies have identified other mechanisms of ATM downregulation via microRNAs and the mTOR pathway (24).…”