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Hedgehog (HH) signaling is important in the pathogenesis of several malignancies. Recently, we described that HH signaling proteins are commonly expressed in diffuse large B-cell lymphoma (DLBCL); however, the functional role of HH pathway in DLBCL has not been explored. Here, we assessed the possibility that HH pathway activation contributes to the survival of DLBCL. We found that HH signaling inhibition induces predominantly cell-cycle arrest in DLBCL cells of germinal center (GC) B-cell type, and apoptosis in DLBCL cells of activated B-cell (ABC) type. Apoptosis after HH signaling inhibition in DLBCL cells of ABC type was associated with downregulation of BCL2; however HH inhibition was not associated with BCL2 downregulation in DLBCL of GC type. Functional inhibition of BCL2 significantly increased apoptosis induced by HH inhibition in DLBCL cells of both types. We also showed that DLBCL cells synthesize, secrete and respond to endogenous HH ligands, providing support for the existence of an autocrine HH signaling loop. Our findings provide novel evidence that dysregulation of HH pathway is involved in the biology of DLBCL and have significant therapeutic implications as they identify HH signaling as a potential therapeutic target in DLBCL, in particular for those lymphomas expressing the HH receptor smoothened. [ABSTRACT FROM AUTHOR]

p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK+ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip(S/L), and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK+ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK+ ALCL patients. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of (ser15)p-p53, suggesting that the (ser15)p-p53 --> AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 --> AMPK --> mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL. [ABSTRACT FROM AUTHOR]

Androulaki A, Drakos E, Hatzianastassiou D, Vgenopoulou S, Gazouli M, Korkolopoulou P, Patsouris E & Dosios T (2004) Histopathology 44, 69–76 Pyothorax-associated lymphoma (PAL): a western case with marked angiocentricity and review of the literature : To report a case of pyothorax-associated lymphoma in a non-immunocompromised 78-year-old man with a 45-year history of tuberculous pleuritis and left pleural effusion. Pyothorax-associated lymphoma is a high-grade non-Hodgkin's lymphoma occurring in 2% of patients with long-standing tuberculous pleuritis and pyothorax. Pyothorax-associated lymphoma is frequently Epstein–Barr virus (EBV)-associated, mainly reported in Japan but exceedingly rare in western countries. : Histology revealed a high-grade, diffuse large B-cell lymphoma with immunoblastic and plasmacytoid features and marked angiocentricity with focal destruction of the vessel walls. Immunohistochemistry revealed a post germinal B-cell phenotype. RNA in-situ hybridization and molecular analysis showed a latent EBV infection and absence of human herpes virus-8 (HHV-8). : Pyothorax-associated lymphoma represents a rare but distinctive type of diffuse large B-cell lymphoma, with characteristic clinico-epidemiological, immunohistological, and biological features. [ABSTRACT FROM AUTHOR]