Expression of cyclin-dependent kinase inhibitor p27(Kip1) in AIDS-related diffuse large-cell lymphomas is associated with Epstein-Barr virus-encoded latent membrane protein 1.
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 p27(Kip1), a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27(Kip1), 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 p27(Kip1) protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27(Kip1) 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 p27(Kip1). Expression of p27(Kip1) 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 p27(Kip1), thus providing a putative mechanistic explanation for the association between LMP1 and p27(Kip1) observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27(Kip1) positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.
Gloghini
Annunziata
A
Division of Pathology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, Italy.
Gaidano
Gianluca
G
Larocca
Luigi M
LM
Pierconti
Francesco
F
Cingolani
Antonella
A
Dal Maso
Luigino
L
Capello
Daniela
D
Franceschi
Silvia
S
Tirelli
Umberto
U
Libra
Massimo
M
Niu
Huifeng
H
Dalla-Favera
Riccardo
R
Carbone
Antonino
A
D029681:Arabidopsis Proteins; D001402:B-Lymphocytes / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors; D019394:Ki-67 Antigen / Q000378:metabolism; D008221:Lymphoid Tissue / Q000378:metabolism; D016483:Lymphoma, AIDS-Related / Q000378:metabolism* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D010641:Phenotype; D010940:Plant Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
D029681:Arabidopsis Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D019394:Ki-67 Antigen; D010940:Plant Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; D000099218:Interferon Regulatory Factor-4; C534696:CCND3 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C118817:SYN1 protein, Arabidopsis