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.

ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells

“…Fas resistance in this system is due to the aberrant up-regulation of FLIP proteins. 26,27 Conversely, ATM expression and function are impaired in many HL cases 7 and in several HL-derived cell lines. 9,29 To test whether ATM loss of function may contribute to Fas resistance through FLIP protein up-regulation, we took advantage of a lymphoma cell line, L428, that has been previously characterized for the aberrant down-regulation of ATM activity 29 and for the aberrant up-regulation of FLIP protein levels.…”

“…6 More interestingly, ATM expression is aberrantly low in several B-and T-cell lymphomas irrespective of A-T genotype. [7][8][9][10] Fas (CD95/APO-1) is a transmembrane protein belonging to the tumor necrosis factor superfamily. Upon binding of Fas ligand or agonistic antibodies, the Fas receptor recruits several cytosolic proteins to form the death-inducing signaling complex (DISC).…”

“…Indeed, the specific down-regulation of FLIP expression by siRNA sensitizes these cells to Fas-induced apoptosis. 26,27 Remarkably, immunohistochemistry studies have shown that most cases of Hodgkin disease are ATM negative, 7 although ATM loss of heterozygosity is a rare event, 28 and therefore alternative mechanisms may account for ATM down-regulation. 29 Taking into account the linkage between Fas impairment and the development of those tumors that are more frequent in A-T patients, the question arises as to whether any relationship exists between Fas and ATM signaling pathways.…”

Molecular Bases of Ataxia Telangiectasia: One Kinase Multiple Functions

“…In particular ATM expression is strongly reduced or lost in some leukaemia and lymphoma [73,[111][112][113]. The modulation of ATM expression levels in breast cancer has been largely investigated.…”

Emerging role of SOX11 in mantle cell lymphoma

“…26,27 ATM, which is involved in the cellular responses to double-strand breaks, is normally expressed in pre-GC B cells and it has been suggested that inactivation of the gene may be involved in malignant transformation. 28,29 In MCL, it has been assumed that Cyclin D1 primarily acts through its role in the cell cycle, controlling the transition of G 1 to S phase by binding and activating cyclin-dependent kinase (CDK) 4 and CDK6 followed by phosphorylation of the retinoblastoma protein and release of the transcription factor E2F. 30 However, in other malignancies several CDK-independent functions of Cyclin D1 have been identified, including interaction with the pro-apoptotic protein BAX 21 and RAD51, 31 the latter impacting DNA repair.…”