Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias.
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.
Starczynski
Jane
J
Department of Histopathology, Birmingham Heartland's Hospital, Birmingham, United Kingdom.
Simmons
William
W
Flavell
Joanne R
JR
Byrd
Phillip J
PJ
Stewart
Grant S
GS
Kullar
Harjit S
HS
Groom
Alix
A
Crocker
John
J
Moss
Paul A H
PA
Reynolds
Gary M
GM
Glavina-Durdov
Meri
M
Taylor
A Malcolm R
AM
Fegan
Christopher
C
Stankovic
Tatjana
T
Murray
Paul G
PG
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
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