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Primary mediastinal B-cell lymphoma (PMBL) is a distinct B-cell lymphoma subtype with unique clinicopathological and molecular features. PMBL cells are characterised by several genetic abnormalities that conduct to the constitutive activation of the Janus kinase 2/signal transducer and activator of transcription 6 (JAK2/STAT6) signalling pathway. Among recurrent genetic changes in PMBL, we previously reported that the XPO1 gene encoding exportin 1 that controls the nuclear export of cargo proteins and RNAs, is mutated (p.E571K) in about 25% of PMBL cases. We therefore hypothesized that STAT6 could be a cargo of XPO1 and that STAT6 cytoplasm/nucleus shuttle could be altered in a subset of PMBL cells. Using immunocytochemistry techniques as well as the proximity ligation assay, we showed that STAT6 bound XPO1 in PBML cell lines and in HEK-293 cells genetically engineered to produce STAT6. Moreover, XPO1-mediated export of STAT6 occurs in cells expressing either a wild-type or the E571K mutated XPO1 protein. [ABSTRACT FROM AUTHOR]

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations. [ABSTRACT FROM AUTHOR]

Abstract: Using a mouse model with the tumor suppressor TRAF3 deleted from B cells, we identified Sox5 as a gene strikingly up-regulated in B lymphomas. Sox5 proteins were not detected in normal or premalignant TRAF3−/− B cells even after treatment with B cell stimuli. The Sox5 expressed in TRAF3−/− B lymphomas represents a novel isoform of Sox5, and was localized in the nucleus of malignant B cells. Overexpression of Sox5 inhibited cell cycle progression, and up-regulated the protein levels of p27 and β-catenin in human multiple myeloma cells. Together, our findings indicate that Sox5 regulates the proliferation of malignant B cells. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) pulsed by tumor antigens have been widely used as tumor vaccines to specifically trigger the cytotoxicity of CD8+ T cells. But the tumor microenviroment with enriched immunosuppressants hampered DC maturation and co-stimulation. CD40/CD40L signaling, one of the most important co-stimulatory molecules is capable of effectively skewing the immune response by promoting DCs maturation and co-stimulation. To establish a novel specific immunotherapeutic approach for the use of DC vaccine in the treatment of B lymphoma, hu-SCID mice bearing B lymphoma were vaccinated by different combination of tumor antigen pulsed DC or imDC vaccines and immune-enhancing agencies such as agonist CD40mAb and T cells. The results of immature DCs combined with agonistic CD40mAb were encouraging with achievement of tumor regression and induction of antigen-specific immune responses. These findings demonstrated the potential utility of imDC-based tumor vaccination combining with agonistic CD40mAb in the treatment of malignant lymphoma. [Copyright &y& Elsevier]

Abstract: The B cell antigen receptor (BCR) composed of the ligand-binding membrane IgM (mIgM) and the signaling component, Ig-α/β, is known to inducibly associate with membrane microdomains rich in cholesterol and sphingolipids, termed lipid rafts. In this study we tested whether the Ig-α/β portion of the BCR has targeting information that allows it to be localized in lipid rafts. In order to do this, we cross-linked the Ig-α/β on the cell surface of the variant B cell line, WEHI 303.1.5, a derivative of the immature murine B cell line WEHI 231 that lacks μ heavy chain and expresses the Ig-α/β on the cell surface by itself. Using two methods to isolate detergent-insoluble, lipid raft-like fractions, we found that Ig-α/β without accompanying mIgM was constitutively located in these raft-like fractions and that the amount was marginally increased after Ig-α/β cross-linking. These results suggest that the Ig-α/β portion of the BCR has the ability to be compartmentalized into raft-like membrane domains even when not associated with mIgM and perhaps this targeting information is normally regulated by the presence of the mIgM portion of the receptor. [Copyright &y& Elsevier]

Clearer evidence for immune surveillance in malignancy and the identification of many new tumour-associated antigens (TAAs) have driven novel vaccine and antibody-targeted responses for therapy in cancer. The exploitation of active immunisation may be particularly favourable for TAA where tolerance is incomplete but passive immunisation may offer an additional strategy where the immune repertoire is affected by either tolerance or immune suppression. This review will consider how to utilise both active and passive types of therapy delivered by T cells in the context of the failure of tumour-specific immunity by presenting cancer patients. This article will outline the progress, problems and prospects of several different vaccine and antibody-targeted approaches for immunotherapy of cancer where proof of principle pre-clinical studies have been or will soon be translated into the clinic. Two examples of vaccination-based therapies where both T cell- and antibody-mediated anti-tumour responses are likely to be relevant and two examples of oncofoetal antigen-specific antibody-directed T cell therapies are described in the following sections: (1) therapeutic vaccination against human papillomavirus (HPV) antigens in cervical neoplasia; (2) B cell lymphoma vaccines including against immunoglobulin idiotype; (3) oncofoetal antigens as tumour targets for redirecting T cells with antibody strategies. [Copyright &y& Elsevier]

Abstract: Peripheral neuropathy is a rare presenting feature of malignant lymphoma, and commonly associated with diagnostic delay. We report a patient with axonal neuropathy revealing primary pleural lymphoma as a late outcome of pulmonary tuberculosis. A 72-year-old-man with a past medical history of pulmonary tuberculosis presented with a 5-month history of axonal neuropathy. The patient complained of chest pain, altered general status. Chest computed tomography (CT) showed pleural tumour invading the chest wall and CT-guided pleural biopsy revealed a B-cell lymphoma. Chemotherapy was not started in consideration of the poor performance status of the patient. Despite corticosteroids, the peripheral neuropathy worsened and the patient died 2 months after the diagnosis of lymphoma. To our knowledge, no previous case of peripheral neuropathy revealing pleural lymphoma has been reported. The diagnosis of lymphoma must be entertained in the presence of peripheral neuropathy of unknown aetiology. Neuropathy associated to lymphoma results from various mechanisms and is characterised by clinical polymorphism. Their prognosis depends on the mechanism of the neuropathy and the severity of the lymphoma. [ABSTRACT FROM AUTHOR]