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1.  Posttransplant Lymphoproliferative Disorders 
Advances in Hematology  2012;2012:230173.
Posttransplant lymphoproliferative disorders (PTLDs) are a group of diseases that range from benign polyclonal to malignant monoclonal lymphoid proliferations. They arise secondary to treatment with immunosuppressive drugs given to prevent transplant rejection. Three main pathologic subsets/stages of evolution are recognised: early, polymorphic, and monomorphic lesions. The pathogenesis of PTLDs seems to be multifactorial. Among possible infective aetiologies, the role of EBV has been studied in depth, and the virus is thought to play a central role in driving the proliferation of EBV-infected B cells that leads to subsequent development of the lymphoproliferative disorder. It is apparent, however, that EBV is not solely responsible for the “neoplastic” state. Accumulated genetic alterations of oncogenes and tumour suppressor genes (deletions, mutations, rearrangements, and amplifications) and epigenetic changes (aberrant hypermethylation) that involve tumour suppressor genes are integral to the pathogenesis. Antigenic stimulation also plays an evident role in the pathogenesis of PTLDs. Plasmacytoid dendritic cells (PDCs) that are critical to fight viral infections have been thought to play a pathogenetically relevant role in PTLDs. Furthermore, regulatory T cells (Treg cells), which are modulators of immune reactions once incited, seem to have an important role in PTLDs where antigenic stimulation is key for the pathogenesis.
doi:10.1155/2012/230173
PMCID: PMC3337580  PMID: 22570658
3.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
doi:10.1038/ng.2468
PMCID: PMC3674561  PMID: 23143597
6.  Aggressive B-Cell Lymphomas 
Advances in Hematology  2012;2012:604603.
doi:10.1155/2012/604603
PMCID: PMC3352139  PMID: 22611401
7.  EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors 
The Journal of Clinical Investigation  2012;122(4):1487-1502.
Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to aggressive, immune-evading monomorphic DLBCL-like tumors in NOD/SCID/γc–/– mice with reconstituted human immune system components. Infection with EBNA3B-knockout EBV (EBNA3BKO) induced expansion of EBV-specific T cells that failed to infiltrate the tumors. EBNA3BKO-infected B cells expanded more rapidly and secreted less T cell–chemoattractant CXCL10, reducing T cell recruitment in vitro and T cell–mediated killing in vivo. B cell lines from 2 EBV-positive human lymphomas encoding truncated EBNA3B exhibited gene expression profiles and phenotypic characteristics similar to those of tumor-derived lines from the humanized mice, including reduced CXCL10 secretion. Screening EBV-positive DLBCL, HL, and BL human samples identified additional EBNA3B mutations. Thus, EBNA3B is a virus-encoded tumor suppressor whose inactivation promotes immune evasion and virus-driven lymphomagenesis.
doi:10.1172/JCI58092
PMCID: PMC3314448  PMID: 22406538
8.  No Evidence of XMRV or MuLV Sequences in Prostate Cancer, Diffuse Large B-Cell Lymphoma, or the UK Blood Donor Population 
Advances in Virology  2011;2011:782353.
Xenotropic murine leukaemia virus-related virus (XMRV) is a recently described retrovirus which has been claimed to infect humans and cause associated pathology. Initially identified in the US in patients with prostate cancer and subsequently in patients with chronic fatigue syndrome, doubt now exists that XMRV is a human pathogen. We studied the prevalence of genetic sequences of XMRV and related MuLV sequences in human prostate cancer, from B cell lymphoma patients and from UK blood donors. Nucleic acid was extracted from fresh prostate tissue biopsies, formalin-fixed paraffin-embedded (FFPE) prostate tissue and FFPE B-cell lymphoma. The presence of XMRV-specific LTR or MuLV generic gag-like sequences was investigated by nested PCR. To control for mouse DNA contamination, a PCR that detected intracisternal A-type particle (IAP) sequences was included. In addition, DNA and RNA were extracted from whole blood taken from UK blood donors and screened for XMRV sequences by real-time PCR. XMRV or MuLV-like sequences were not amplified from tissue samples. Occasionally MuLV gag and XMRV-LTR sequences were amplified from Indian prostate cancer samples, but were always detected in conjunction with contaminating murine genomic DNA. We found no evidence of XMRV or MuLV infection in the UK blood donors.
doi:10.1155/2011/782353
PMCID: PMC3265314  PMID: 22312352
9.  Small intestinal presentation of nodular lymphocyte-predominant Hodgkin lymphoma with T cell/histiocyte-rich B cell lymphoma-like areas—with review of literature on extranodal presentation of this disease 
Journal of Hematopathology  2010;3(1):29-34.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), accounts for ∼5% of all cases of Hodgkin lymphoma and is characterized by involvement of the peripheral lymph nodes. NLPHL occurs in young adults and is associated with frequent relapses. In 3% to 7% of cases, NLPHL progresses to a diffuse large B cell lymphoma. Furthermore, a proportion of NLPHL also have areas with features of T cell/histiocyte-rich large B cell lymphoma (THRLBCL), either at presentation or on follow-up. Here, we describe a 32-year-old man who presented to the emergency department with small bowel perforation. The resected small bowel showed full-thickness mural ulceration and involvement by a lymphoma with features of NLPHL that also had areas resembling THRLBCL. The patient had axillary lymphadenopathy, biopsy of which showed NLPHL with focal THRLBCL-like areas. Such a lymphoma presenting as small intestinal lesion/perforation has not been reported in the literature before. We take this opportunity to review the literature on extranodal presentations of NLPHL and discuss the natural history of this disease.
doi:10.1007/s12308-010-0056-6
PMCID: PMC2883906  PMID: 21436871
Lymphoma; Hodgkin lymphoma; Diffuse large B cell lymphoma; Gray zone lymphoma; Immunohistochemistry
10.  p27Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo†  
Molecular and Cellular Biology  2006;26(16):6170-6184.
To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1−/−; p130−/− mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1−/− counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1−/−; p130−/− animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1−/− splenocytes. The finding that the p27Kip1−/−; p130−/− splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.
doi:10.1128/MCB.02182-05
PMCID: PMC1592787  PMID: 16880527
11.  The Alteration of Lipid Metabolism in Burkitt Lymphoma Identifies a Novel Marker: Adipophilin 
PLoS ONE  2012;7(8):e44315.
Background
Recent evidence suggests that lipid pathway is altered in many human tumours. In Burkitt lymphoma this is reflected by the presence of lipid droplets which are visible in the cytoplasm of neoplastic cells in cytological preparations. These vacuoles are not identifiable in biopsy section as lipids are “lost” during tissue processing.
Methods and Results
In this study we investigated the expression of genes involved in lipid metabolism, at both RNA and protein level in Burkitt lymphoma and in other B-cell aggressive lymphoma cases. Gene expression profile indicated a significant over-expression of the adipophilin gene and marked up-regulation of other genes involved in lipid metabolism in Burkitt lymphoma. These findings were confirmed by immunohistochemistry on a series od additional histological samples: 45 out of 47 BL cases showed strong adipophilin expression, while only 3 cases of the 33 of the not-Burkitt lymphoma category showed weak adipophilin expression (p<0.05).
Conclusions
Our preliminary results suggest that lipid metabolism is altered in BL, and this leads to the accumulation of lipid vacuoles. These vacuoles may be specifically recognized by a monoclonal antibody against adipophilin, which may therefore be a useful marker for Burkitt lymphoma because of its peculiar expression pattern. Moreover this peptide might represent an interesting candidate for interventional strategies.
doi:10.1371/journal.pone.0044315
PMCID: PMC3432109  PMID: 22952953

Results 1-11 (11)