title: Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias.
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.
authors.affiliation: Department of Histopathology, Birmingham Heartland's Hospital, Birmingham, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Starczynski
authors.forename: William
authors.initials: W
authors.lastname: Simmons
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Flavell
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: Harjit S
authors.initials: HS
authors.lastname: Kullar
authors.forename: Alix
authors.initials: A
authors.lastname: Groom
authors.forename: John
authors.initials: J
authors.lastname: Crocker
authors.forename: Paul A H
authors.initials: PA
authors.lastname: Moss
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Meri
authors.initials: M
authors.lastname: Glavina-Durdov
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Christopher
authors.initials: C
authors.lastname: Fegan
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases