No description available.

No description available.

No description available.

Murine plasmacytoma models human cancers that involve deregulation of MYC. Overexpression and duplication of the immature colon carcinoma transcript 1 gene, Ict1, along with MYC deregulation may contribute to the aggressive mechanism for disease development in fast-onset mouse plasmacytomas. This study looks at Ict1 and c-MYC overexpression in mouse PreBmycER cells that serve as a cell culture model for MYC-dependent plasmacytomagenesis. An Ict1 inducible vector was transfected into the mouse PreBmycER cell line that contains inducible c-MYC. This allowed us to examine the effect of overexpression of ICT1 and c-MYC proteins simultaneously or each separately, on selected hallmark cancer cell traits such as increased proliferation, evasion of apoptosis and increased genomic instability. An increase in the number of cells in the S-phase was observed by 15 % and up to 20 % at 24 and 36 hours respectively, and cell doubling time shortened by almost 2 hours at 24 hours during peak ICT1 and c-MYC overexpression. Although, no noticeable change in apoptosis levels, or large scale genomic alterations were detected up to 96 hours post-ICT1 and c-MYC peak-overexpression, genomic instability was observed when MYC protein was overexpressed with or without ICT1 protein overexpression. Extrachromosomal elements increased in number and size during conditional MYC deregulation, and most of these elements (25 %) classified as Chromosome 11. These findings support Ict1 as a candidate gene that is selected for by MYC-deregulation during plasmacytomagenesis, and show promise that the experimental model of induced MYC and ICT1 overexpression in mouse PreB cells, deserves further investigation, specifically with in vivo studies. / October 2016

Mechanisms underlying the interactions between the proteasome inhibitor carfilzomib and HDAC inhibitors were examined in both germinal center (GC) and activated B-cell (ABC) subtypes of human diffuse large B-cell lymphoma (DLBCL). Simultaneous exposure to minimally toxic concentrations of carfilzomib and HDAC inhibitor vorinostat resulted in the release of mitochondrial pro-apoptotic proteins SMAC and cytochrome c, pro-apoptotic caspase activation, and synergistic induction in apoptosis in both ABC and GC DLBCL subtypes. These events were associated with a marked increase in the stress kinase JNK, ROS generation, G2-M cell cycle arrest, as well as induction of DNA damage. Genetic knockdown of JNK resulted in a significant decrease in carfilzomib/vorinostat induced cell death. Co-administration of the antioxidant MnTBAP significantly reduced carfilzomib/vorinostat induced cell death, and resulted in a marked decrease in caspase-3 as well as a striking decrease in JNK phosphorylation. Tumor growth reduction was also observed in animal models that were treated with a combined regimen of carfilzomib and vorinostat. Finally, the combined treatment of carfilzomib/vorinostat was able to overcome any cross-resistance to carfIlzomib in bortezomib resistant cells. Collectively, these finding indicate that the combined regimen of carfilzomib and HDAC inhibitors promote lethality in ABC and GC human DLBCL cells by a variety of mechanisms both in vitro and in vivo. Further studies are necessary for clinical development of this drug regimen.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Anatomical Pathology Johannesburg, 2016 / Introduction: Plasmablastic lymphoma (PBL) is an uncommon variant of aggressive B-cell non-Hodgkin lymphoma that occurs in immune-compromised individuals, most commonly secondary to HIV infection. This tumour classically occurs in the oral cavity but has also been described in a variety of extra-oral locations. This is a clinicopathological study of 45 cases of extra-oral PBL (EPBL). Aim: To define the clinical parameters, histology and immunophenotypic features of extra-oral plasmablastic lymphoma (EPBL) and assess the extent to which Epstein–Barr virus (EBV) is associated with this tumour. Materials and Methods: This retrospective study on archival cases of EPBL included the patients‟ age, gender, race, HIV status where available and the site of tumour presentation. Of 49 archival cases retrieved, 4 were discounted owing to reclassification as diffuse large B-cell lymphoma (1 case), multiple myeloma or extramedullary plasma cell tumour (3 cases). The remaining 45 cases were reviewed histologically and classified according to whether they displayed a pure plasmablastic (PBm) morphology or a plasmablastic morphology with plasmacytic differentiation (PBm+PCd), and assessed immunohistochemically with CD45 (LCA), CD20, CD79a, PAX5, CD138, MUM1, BLIMP1, VS38c, Ki-67, BCL6, CD10, HHV8 and CyclinD1 using standard automated procedures. The presence of EBV was assessed by chromogenic in-situ hybridisation. Ethical clearance was obtained (M10750 and M120993). Results: 27of the 45 cases had a pure plasmablastic morphology. The remaining 18 cases showed plasmacytic differentiation. There was no site predilection according to histological pattern. 60% of the tumours were reported in males and 40% in females and all were black African patients. The anus was the favoured extra-oral site of presentation (13 of 45 cases, 28%), followed by soft tissue (11 of 45 cases, 24%). There was no significant difference in the age of presentation between males (38.5 years) and females (35.4 years). Of the 18 patients of known HIV status, 17 were HIV positive (94%). The immunohistochemical profile of EPBL recapitulated that found for both oral and extra-oral PBL in the literature, except for CD45 (leucocyte common antigen) which signalled positively in a higher percentage of cases. 36 of 42 cases (85.7%) were positive for CD45. The positive membrane signal for CD45 was of variable intensity, between 5 and 100% of tumour cells. EBV was positive by in situ hybridisation in 37 of 40 cases tested (92.5%). Conclusion: EPBL is identical to its oral counterpart in gender and age distribution, HIV status, morphological appearances, immunophenotypic profile and association with EBV. The high association with EBV as assessed by in-situ hybridisation studies mirrors that of oral-based PBL reported in the literature. EPBL should be regarded as the same tumour as that arising within the oral cavity. A peculiarity observed within this case cohort is the high level of expression of CD45 (leucocyte common antigen). This has been reported to be of low or near absent expression in most cases of PBL, as defined by the 2008 WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. / MT2016

The transcription factor NF-κB is a key regulator in many physiological processes, including innate and adaptative immune responses, inflammation and lymphoid organ development. NF-κB plays a crucial role in the development of B and T cells, by maintaining the cell death/survival equilibrium and therefore, constitutive activation of NF-κB is thought to contribute to the development and/or progression of B and T cell malignancies. The nfκb2 gene is frequently involved in chromosomal translocations associated with the development of various lymphomas and leukemias. These rearrangements all lead to the production of C-terminally truncated p100 proteins lacking variable portions of the ankyrin repeats domain, suggesting that this common feature may be involved in tumor development. However, whereas the oncogenic potential of such proteins is well established, the underlying mechanisms remain poorly understood. The aim of this work was to better understand these mechanisms by which such alterations contribute to lymphomagenesis. We then choose to investigate the functions of the protein Hut78 as representative of these p100ΔC mutants found in tumor cells. We identified mmp9 as a target gene of p52 and p52-producing NF-κB2 mutants and defined p52 as a key molecule for the invasive potential of lymphoma-derived cells harboring enhanced activity of the NF-κB alternative pathway. Moreover, we found that this p52/Hut78-mediated transcriptional induction of MMP9 involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes by p52 on the mmp9 gene promoter. Taken together, our results provide further insights into the oncogenic potential of the truncated p100 proteins, and by extension, will help to better understand how mutated IκB proteins contribute to deregulated NF-κB activities in haematological disorders.

We conducted a retrospective review of discordant pathology for lymphoma patients treated at the Princess Margaret Hospital between 2000 and 2003. We identified 2818 lymphoma patients of which 1567 (38%) met inclusion criteria with 167 discordant cases (discordance rate 15.7%). Six reviewers blinded to clinical management rated potential for harm on a minimal to severe scoring. The majority (67.6%) received a rating of moderate to severe. Review of actual clinical management revealed unnecessary surgical procedures, incorrect chemotherapy and under or over treatment of patients. For discordant cases, 8.4% were identified as having severe actual harm. This means that 1/6 patients diagnosed with lymphoma may have a change in diagnosis after pathologic review, 1/9 will have discordance with the potential to cause moderate to severe consequences, and 1/75 will experience significant clinical harm. We conclude that pathologic discordance in lymphoma is common and can lead to patient harm.

We conducted a retrospective review of discordant pathology for lymphoma patients treated at the Princess Margaret Hospital between 2000 and 2003. We identified 2818 lymphoma patients of which 1567 (38%) met inclusion criteria with 167 discordant cases (discordance rate 15.7%). Six reviewers blinded to clinical management rated potential for harm on a minimal to severe scoring. The majority (67.6%) received a rating of moderate to severe. Review of actual clinical management revealed unnecessary surgical procedures, incorrect chemotherapy and under or over treatment of patients. For discordant cases, 8.4% were identified as having severe actual harm. This means that 1/6 patients diagnosed with lymphoma may have a change in diagnosis after pathologic review, 1/9 will have discordance with the potential to cause moderate to severe consequences, and 1/75 will experience significant clinical harm. We conclude that pathologic discordance in lymphoma is common and can lead to patient harm.

In this study, the effects of antagonists to the cannabinoid receptors in MCL cell lines were studied. Results presented in this study show that signalling through cannabinoid receptor with antagonists such as SR141716, SR144528 decreases cell viability but hemopressin when analyzing with XTT. The decrease in cell viability by SR141716 is caused by apoptosis triggered after 5 hours of treatment. The CB1 expression was confirmed in all MCL cell lines tested via western blotting but the expression of CB2 and GPR55 – another receptor to which SR141716 has affinity - was not confirmed due to lack of reliable antibodies. Specific agonist to GPR55 – LPI (l-α-lysophosphatidylinositol) showed different response compared to SR141716 which suggests that the effect seen by SR141716 was not induced through GPR55. The effect induced by CB1/CB2 agonist AEA is shown to be neither through CB1 or CB2 alone but possibly on another receptor yet to be described.