IntroductionMantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin lymphoma whose normal counterpart is likely represented by pre-germinal center, naive B cells that populates the mantle zone of lymph nodes. 1 MCL is characterized by advanced stage at presentation, frequent extranodal localization, and aggressive clinical behavior, with poor response to conventional therapeutic regimens and a very unfavorable prognosis, even when the disease is treated with high-dose therapy and autologous bone marrow transplantation. 1 More than 95% of MCLs show the t(11;14) (q13;q32) translocation, which results in a juxtaposition of the CCND1 gene locus to the immunoglobulin heavy chain promoter and the subsequent cyclin D1 overexpression, 1,2 leading to the deregulation of the cyclin D/Rb pathway. Cyclin D1 deregulation, however, is not sufficient for lymphomagenesis; cooperation with microenvironmental stimuli, such as IL-4, IL-10, and CD40 activation, as well as additional genetic changes, are probably required to induce and sustain the transformed phenotype of mantle cells. Indeed, defects involving inhibitors of G 1 cell-cycle progression, such as p53, p27 Kip1 , p16 INK4a , and p15 INK4 , may also occur in MCL. 3,4 More recently, gene-expression profiling and proteomic studies demonstrated that MCL cells carry a profound deregulation of multiple genes and pathways that are involved in the control of cell growth and survival. 5,6 Despite these advances, however, only limited information is available on the mechanisms responsible for the constitutive activation of critical signaling pathways and their functional significance. Elucidation of these issues is of particular relevance to identify and exploit tumor-specific molecular signatures for new treatment strategies.Among the signaling pathways that may be deregulated in MCL cells, the phosphatidyl-inositol-3 kinase (PI3-K)/Akt pathway has recently attracted great interest as a possible therapeutic target. The PI3-K pathway is activated by a wide range of tyrosine kinase growth factor receptors and is the major activator of Akt, a serine/threonine protein kinase that modulates the function of a variety of downstream substrates involved in the regulation of cell-cycle progression, differentiation, transcription, translation, cell survival, and angiogenesis. Activation of PI3-K generates the membrane lipid phosphatidylinositol-trisphosphate (PIP3), which favors the recruitment of Akt to the plasma membrane, where the Akt kinase is activated upon phosphorylation by 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Akt activation is counteracted by PTEN, a lipid phosphatase that dephosphorylates PIP3, whose expression is lost in a variety of tumor cells. 7 Moreover, recent evidence also indicates that PTEN can be inactivated by phosphorylation of serine 380/threonine 382/383 on its carboxy-terminal regulatory domain. [8][9][10] Nevertheless, the role of phosphorylated PTEN in human tumors has been poorly investigated so far. Submitted July 26, 2007; accepted Marc...

Transformation of primary B lymphocytes by Epstein-Barr virus requires the establishment of a strictly latent infection, the expression of several latent viral proteins, and sustained telomerase activity. Our previous findings indicated that induction of hTERT, the rate-limiting catalytic unit of the telomerase complex, was associated with the expression of the viral latent membrane protein 1 (LMP1). In the present study, we demonstrate that ectopic expression of LMP1 in BJAB and Ramos B cells resulted in an increase of hTERT transcripts, thus suggesting that LMP1 acts at the transcriptional level. This was confirmed by transient expression of a luciferase reporter plasmid containing the hTERT promoter cotransfected with an LMP1-expressing vector or transfected into B cells in which LMP1 expression was inducible. Consistently, silencing of LMP1 by small interfering RNA resulted in a reduction of hTERT transcripts. We also provide evidence indicating that LMP1-induced hTERT activation is independently mediated by NF-B and by mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways, whereas CD40, Akt, and mTOR signaling has no involvement. Moreover, our results do not support a role for c-Myc in mediating these effects on hTERT, since ectopic expression of LMP1 did not upregulate c-Myc and silencing of this oncogene or E box mutagenesis failed to inhibit LMP1-induced hTERT activation. These findings indicate that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity, thus confirming the pleiotropic nature of this viral oncoprotein.Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts by colonizing memory B lymphocytes. EBV has a potent transforming ability, being able to efficiently induce blast transformation and uncontrolled proliferation of infected B lymphocytes in vitro. Available evidence, particularly the presence of EBV genomes and the constant expression of viral proteins, strongly supports a relevant role for EBV in the pathogenesis of a wide spectrum of human malignancies, most of which are derived from B lymphocytes (12, 44). Latently EBV-infected B cells may express a defined set of latency genes that include those encoding six nuclear antigens (EBNAs) and three latent membrane proteins (latent membrane protein 1 [LMP1], LMP2A, and LMP2B). Among the EBV latency gene products, LMP1 is considered the strongest oncoprotein, being essential for immortalization of B cells. The N terminus and the six transmembrane domains of the protein form aggregates in the cytoplasmic membrane, allowing LMP1 to act like a constitutively activated receptor (5, 15). Indeed, LMP1 shares functional properties with members of the tumor necrosis factor (TNF) receptor superfamily, particularly CD40, and induces the expression of NF-B through activation of the TNF receptor-associated factor signaling pathway (31,40). Cons...

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