Expression of cyclin-dependent kinase inhibitor p27Kip1 in AIDS-related diffuse large-cell lymphomas is associated with Epstein-Barr virus-encoded latent membrane protein 1

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Abstract

Knowledge of the role of cell-cycle regulators in the pathogenesis of acquired immune deficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHLs) is scarce. Here we analyzed 86 systemic AIDS-NHLs and 20 AIDS-primary central nervous system lymphomas for expression of p27Kip1, a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27Kip1, the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage. We report that AIDS-immunoblastic lymphomas (AIDS-IBLs), either systemic or primarily localized to the central nervous system, consistently express p27Kip1 protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27Kip1 to inhibit the cell cycle in AIDS-IBL. Conversely, the remaining systemic AIDS-NHLs and AIDS-primary central nervous system lymphomas preferentially fail to express p27Kip1. Expression of p27Kip1 in Epstein-Barr virus-positive AIDS-NHLs generally associates with latent membrane protein 1 (LMP1) expression and is related to a late stage of B-cell differentiation, characterized by the BCL-6-/ MUM1+/syn-1± phenotypic profile, whereas it seems to be unrelated to the expression of cellular cyclins. In B cells in vitro, induction of LMP-1 expression under the control of inducible promoters up-regulates expression of p27Kip1, thus providing a putative mechanistic explanation for the association between LMP1 and p27Kip1 observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27Kip1 positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.

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Gloghini, A., Gaidano, G., Larocca, L. M., Pierconti, F., Cingolani, A., Dal Maso, L., … Carbone, A. (2002). Expression of cyclin-dependent kinase inhibitor p27Kip1 in AIDS-related diffuse large-cell lymphomas is associated with Epstein-Barr virus-encoded latent membrane protein 1. American Journal of Pathology, 161(1), 163–171. https://doi.org/10.1016/S0002-9440(10)64168-5

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