Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias

Jane Starczynski, William Simmons, Joanne R. Flavell, Phillip J. Byrd, Grant S. Stewart, Harjit S. Kullar, Alix Groom, John Crocker, Paul A.H. Moss, Gary M. Reynolds, Meri Glavina-Durdov, A. Malcolm R. Taylor, Christopher Fegan, Tatjana Stankovic, Paul G. Murray

Research output: Contribution to journalArticlepeer-review

Abstract

The ataxia telangiectasia mutated (ATM) protein plays a central role in the cellular response to DNA double-strand breaks (DSBs). Developmentally programmed DSBs are restricted to cellular subsets within lymphoid tissues and we asked whether ATM expression is differentially regulated during lymphoid differentiation. We showed that immature B cells in bone marrow and immature T cells of the thymic cortex were negative or weakly ATM-positive. T cells of thymic medulla and peripheral tissues strongly expressed ATM. High levels of ATM were present in the B lymphocytes of the mantle zone and in plasma cells, while the majority of germinal center B cells were negative or weakly labeled. Therefore, ATM expression appears to be down-regulated at those stages of lymphoid development where physiological DNA DSBs occur. In B-chronic lymphocytic leukemia and mantle cell lymphoma we observed two categories: ATM-negative tumors, most likely reflecting the presence of ATM mutation, and tumors with abundant ATM expression. Most follicular center-cell lymphomas and diffuse large B-cell lymphomas, which rarely show inactivation of the ATM gene, were negative or weakly ATM-positive. Tumor cells from most cases of Hodgkin's disease were ATM-negative. Therefore, unless ATM inactivation occurs, ATM expression in lymphoid tumors is likely to reflect their cellular origin. As a result, immunostaining to identify lymphoid neoplasias with ATM inactivation might only be feasible for tumors derived from the stages where ATM is constitutively highly expressed.

Original languageEnglish
Pages (from-to)423-432
Number of pages10
JournalAmerican Journal of Pathology
Volume163
Issue number2
DOIs
Publication statusPublished - 1 Aug 2003
Externally publishedYes

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