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

S. Bose, J. Starczynski, M. Chukwuma, K. Baumforth, W. Wei, S. Morgan, P. Byrd, J. Ying, R. Grundy, J. R. Mann, Q. Tao, A. M.R. Taylor, P. G. Murray, T. Stankovic

    Research output: Contribution to journalArticle

    10 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)329-336
    Number of pages8
    JournalJournal of Pathology
    Volume213
    Issue number3
    DOIs
    StatePublished - Nov 1 2007

    Keywords

    • ATM
    • Hodgkin Reed-Sternberg cells
    • Hodgkin's lymphoma

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine

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  • Cite this

    Bose, S., Starczynski, J., Chukwuma, M., Baumforth, K., Wei, W., Morgan, S., Byrd, P., Ying, J., Grundy, R., Mann, J. R., Tao, Q., Taylor, A. M. R., Murray, P. G., & Stankovic, T. (2007). Down-regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation. Journal of Pathology, 213(3), 329-336. https://doi.org/10.1002/path.2232