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author:("bradburn, Amy")
1.  Genetics of follicular lymphoma transformation 
Cell reports  2014;6(1):130-140.
Summary
Follicular lymphoma (FL) is an indolent disease, but 30-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, here we show that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and anti-apoptotic genes are introduced early in the common precursor, while tFL is specifically associated with alterations deregulating cell-cycle progression and DNA-damage responses (CDKN2A/B, MYC, TP53), as well as with aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B-cell-type de novo DLBCL, but also displays unique combinations of altered genes, with diagnostic and therapeutic implications.
doi:10.1016/j.celrep.2013.12.027
PMCID: PMC4100800  PMID: 24388756
2.  Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B Cell Lymphoma 
Cancer discovery  2013;3(9):1002-1019.
Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. The combination was well tolerated and yielded a high rate of complete remission. Pre and post azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.
doi:10.1158/2159-8290.CD-13-0117
PMCID: PMC3770813  PMID: 23955273
Non-Hodgkin lymphoma; epigenetic; DNA methylation; DNMT inhibitor; chemoresistance
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
4.  Expression of the Follicular Lymphoma Variant Translocation 1 Gene in Diffuse Large B-Cell Lymphoma Correlates With Subtype and Clinical Outcome 
Sphingolipids serve an important role as effector molecules in signaling pathways bearing on apoptosis and cell survival. The balance between proapoptotic ceramide and prosurvival sphingosine-1-phosphate, sometimes termed the “sphingolipid rheostat,” has received particular attention. Less well studied is the role of the follicular lymphoma variant translocation 1 (FVT1) gene, which was identified through its involvement in an atypical follicular lymphoma translocation and which encodes an enzyme in the synthetic pathway of ceramide. We investigated the expression of FVT1 in a variety of B-cell non-Hodgkin lymphomas and found that FVT1 is significantly underexpressed by germinal center–type diffuse large B-cell lymphoma (DLBCL) when compared with non–germinal center–type DLBCL, follicular lymphoma, and normal tonsil control samples. Increased expression of FVT1 correlated with decreased survival, suggesting that changes in the expression of FVT1 and in the concentrations of bioactive sphingolipids may be important in the pathogenesis and treatment of some types of DLBCL.
doi:10.1309/AJCP12HIRWSRQLAN
PMCID: PMC3614404  PMID: 19019774
Follicular lymphoma variant translocation 1 gene; FVT1; Lymphoma; Sphingolipids; Ceramide
7.  Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma 
Nature Genetics  2011;43(9):830-837.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. While a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains on average more than 30 clonally represented gene alterations/case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2, 24% of cases) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
doi:10.1038/ng.892
PMCID: PMC3297422  PMID: 21804550
8.  BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell like diffuse large B cell lymphoma 
Cancer cell  2010;18(6):568-579.
SUMMARY
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal centre B cell like (GCB) and activated B cell like (ABC) DLBCL. These phenotypic subtypes segregate with largely unique genetic lesions, suggesting the involvement of different pathogenetic mechanisms. In this report, we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in ~53% of ABC-DLBCL. In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL. These results demonstrate that BLIMP1 is a bona fide tumor suppressor gene whose loss contributes to lymphomagenesis by blocking plasma cell differentiation.
doi:10.1016/j.ccr.2010.10.030
PMCID: PMC3030476  PMID: 21156281
9.  NK/T cell non-Hodgkin lymphoma in a HIV-positive patient 
Journal of Hematopathology  2010;3(1):35-40.
NK/T lymphomas have rarely been reported in HIV/AIDS patients. Here we report a case of a 37-year-old woman, with AIDS and a recent diagnosis of Kaposi sarcoma in a mesenteric lymph node, who presented with extra-ocular nerve palsies and gastrointestinal bleeding. A small intestine resection specimen revealed an extra-nodal NK/T cell lymphoma, nasal type. The unique presentation of this rare and aggressive lymphoma in the setting of AIDS and Kaposi sarcoma underscores the importance of maintaining a broad differential diagnosis when evaluating a malignant neoplasm from a HIV-positive patient.
doi:10.1007/s12308-010-0057-5
PMCID: PMC2883910  PMID: 21373175
Natural killer/T cell lymphoma; AIDS; HIV; Kaposi sarcoma
10.  Multicenter Analysis of 80 Solid Organ Transplantation Recipients With Post-Transplantation Lymphoproliferative Disease: Outcomes and Prognostic Factors in the Modern Era 
Journal of Clinical Oncology  2010;28(6):1038-1046.
Purpose
Adult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined.
Methods
We examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) –related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008).
Results
Eighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P < .0001) and 33% (P = .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P = .01; OS, 3.61; P = .04), bone marrow involvement (PFS, 2.95; P = .03; OS, 3.14; P = .03), and hypoalbuminemia (PFS, 2.96; P = .05; OS, 3.64; P = .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, ≥ 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P < .0001).
Conclusion
This large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.
doi:10.1200/JCO.2009.25.4961
PMCID: PMC2834429  PMID: 20085936
11.  Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation 
Cancer research  2009;69(22):8686-8692.
S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology and migration in many cell types in vitro. Here we report that S1P2−/− mice develop clonal B cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC) derived diffuse large B cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28/106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2−/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy.
doi:10.1158/0008-5472.CAN-09-1110
PMCID: PMC2973841  PMID: 19903857
diffuse large cell lymphoma; G-protein coupled receptor; somatic hypermutation
12.  Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma 
Nature  2009;459(7247):717-721.
Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL1. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex2. However, except for a small fraction of cases3, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is most commonly affected, with ~30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses.
doi:10.1038/nature07968
PMCID: PMC2973325  PMID: 19412164
13.  Immunophenotypic Analysis of AIDS-Related Diffuse Large B-Cell Lymphoma and Clinical Implications in Patients From AIDS Malignancies Consortium Clinical Trials 010 and 034 
Journal of Clinical Oncology  2009;27(30):5039-5048.
Purpose
Diffuse large B-cell lymphoma (DLBCL) represents a clinically heterogeneous disease. Models based on immunohistochemistry predict clinical outcome. These include subdivision into germinal center (GC) versus non-GC subtypes; proliferation index (measured by expression of Ki-67), and expression of BCL-2, FOXP1, or B-lymphocyte-induced maturation protein (Blimp-1)/PRDM1. We sought to determine whether immunohistochemical analyses of biopsies from patients with DLBCL having HIV infection are similarly relevant for prognosis.
Patients and Methods
We examined 81 DLBCLs from patients with AIDS in AMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) and AMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plus rituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data, Epstein-Barr virus (EBV) positivity, and CD4 counts.
Results
The GC and non-GC subtypes of DLBCL did not differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could be found in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival. Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients with AIDS-related DLBCL.
Conclusion
These data indicate that with current treatment strategies for lymphoma and control of HIV infection, commonly used immunohistochemical markers may not be clinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical marker was found to be Ki-67, where a higher proliferation index was associated with better survival, suggesting a better response to therapy in patients whose tumors had higher proliferation rates.
doi:10.1200/JCO.2008.20.5450
PMCID: PMC2799056  PMID: 19752343
15.  HIV-1 evades virus-specific IgG2 and IgA class switching by targeting systemic and intestinal B cells via long-range intercellular conduits 
Nature immunology  2009;10(9):1008-1017.
Contact-dependent communication between immune cells generates protection, but also facilitates viral spread. We found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type-1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients harboring Nef-deficient virions, our data suggest that HIV-1 exploits intercellular highways as a “Trojan horse” to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.
doi:10.1038/ni.1753
PMCID: PMC2784687  PMID: 19648924
16.  Patients with Epstein Barr virus positive lymphomas have decreased CD4+ T cell responses to the viral nuclear antigen 1 
Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV associated lymphomas express in most cases only three or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV specific CD4+ T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1 specific CD4+ T cell responses and have slightly altered EBNA1 specific antibody titers at diagnosis. In contrast, the majority of EBV negative lymphoma patients had detectable IFNγ expression and proliferation by CD4+ T cells in response to EBNA1, and carry EBNA1 specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8+ T cell frequencies in both cohorts. Patients with EBV positive and negative lymphomas did not differ in T cell responses in influenza specific CD4+ T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1 specific immune control in EBV associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.
doi:10.1002/ijc.23845
PMCID: PMC2605183  PMID: 18781564
EBNA1; CD4+ T cells; Hodgkin's lymphoma
17.  Priming of protective T cell responses against virus-induced tumors in mice with human immune system components 
The Journal of Experimental Medicine  2009;206(6):1423-1434.
Many pathogens that cause human disease infect only humans. To identify the mechanisms of immune protection against these pathogens and also to evaluate promising vaccine candidates, a small animal model would be desirable. We demonstrate that primary T cell responses in mice with reconstituted human immune system components control infection with the oncogenic and persistent Epstein-Barr virus (EBV). These cytotoxic and interferon-γ–producing T cell responses were human leukocyte antigen (HLA) restricted and specific for EBV-derived peptides. In HLA-A2 transgenic animals and similar to human EBV carriers, T cell responses against lytic EBV antigens dominated over recognition of latent EBV antigens. T cell depletion resulted in elevated viral loads and emergence of EBV-associated lymphoproliferative disease. Both loss of CD4+ and CD8+ T cells abolished immune control. Therefore, this mouse model recapitulates features of symptomatic primary EBV infection and generates T cell–mediated immune control that resists oncogenic transformation.
doi:10.1084/jem.20081720
PMCID: PMC2715061  PMID: 19487422
18.  Role of Defective Oct-2 and OCA-B Expression in Immunoglobulin Production and Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation in Primary Effusion Lymphoma▿  
Journal of Virology  2009;83(9):4308-4315.
Primary effusion lymphoma (PEL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8). Despite having a genotype and gene expression signature of highly differentiated B cells, PEL does not usually express surface or cytoplasmic immunoglobulin (Ig). We show the lack of Oct-2 and OCA-B transcription factors to be responsible, at least in part, for this defect in Ig production. Like Ig genes, ORF50, the key regulator of the switch from latency to lytic reactivation, contains an octamer motif within its promoter. We therefore examined the impact of Oct-2 and OCA-B on ORF50 activation. The binding of Oct-1 to the ORF50 promoter has been shown to significantly enhance ORF50 transactivation. We found that Oct-2, on the other hand, inhibited ORF50 expression and consequently lytic reactivation by competing with Oct-1 for the octamer motif in the ORF50 promoter. Our data suggest that Oct-2 downregulation in infected cells would be favorable to KSHV in allowing for efficient viral reactivation.
doi:10.1128/JVI.02196-08
PMCID: PMC2668464  PMID: 19224997
19.  Lymphoma Diagnosis and Plasma Epstein-Barr Virus Load during Vicriviroc Therapy: Results of the AIDS Clinical Trials Group A5211 
Background
Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA.
Methods
Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction.
Results
Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels.
Conclusions
CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.
doi:10.1086/597007
PMCID: PMC2756462  PMID: 19191652
20.  CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors  
The Journal of Clinical Investigation  2008;118(6):2111-2120.
Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10–/–CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133– population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133– metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133– cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24–), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133– subset, which is also capable of tumor initiation in NOD/SCID mice.
doi:10.1172/JCI34401
PMCID: PMC2391278  PMID: 18497886
21.  Distinct Subsets of Primary Effusion Lymphoma Can Be Identified Based on Their Cellular Gene Expression Profile and Viral Association 
Journal of Virology  2005;79(2):1244-1251.
Primary effusion lymphomas (PELs) are specifically associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection and most frequently occur in human immunodeficiency virus (HIV)-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant Epstein-Barr virus (EBV) infection, suggesting that EBV is an important pathogenetic cofactor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. Our results show that many genes, including cell cycle and signal transduction regulators, are differentially expressed between KSHV-positive PELs and KSHV-negative lymphomatous effusions and also between KSHV-positive, EBV-positive and KSHV-positive, EBV-negative PELs. Our results confirm that KSHV plays an important role in the pathogenesis of PELs, as its presence selects for a very distinct cellular gene expression category and a clearly different lymphoma type. Within the KSHV-positive PELs, the effect of EBV is more subtle but nevertheless clear.
doi:10.1128/JVI.79.2.1244-1251.2005
PMCID: PMC538532  PMID: 15613351
22.  Germinal Center B Cells Regulate Their Capability to Present Antigen by Modulation of HLA-DO 
The Journal of Experimental Medicine  2002;195(8):1063-1069.
Peptide acquisition by MHC class II molecules is catalyzed by HLA-DM (DM). In B cells, HLA-DO (DO) inhibits or modifies the peptide exchange activity of DM. We show here that DO protein levels are modulated during B cell differentiation. Remarkably, germinal center (GC) B cells, which have low levels of DO relative to naive and memory B cells, are shown to have enhanced antigen presentation capabilities. DM protein levels also were somewhat reduced in GC B cells; however, the ratio of DM to DO in GC B cells was substantially increased, resulting in more free DM in GC B cells. We conclude that modulation of DM and DO in distinct stages of B cell differentiation represents a mechanism by which B cells regulate their capacity to function as antigen-presenting cells. Efficient antigen presentation in GC B cells would promote GC B cell–T cell interactions that are essential for B cells to survive positive selection in the GC.
doi:10.1084/jem.20012059
PMCID: PMC2193692  PMID: 11956297
HLA-DO; HLA-DM; antigen processing; MHC class II; germinal center B cells
23.  Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration 
Journal of Clinical Investigation  2000;106(4):511-521.
Emerging data suggest that VEGF receptors are expressed by endothelial cells as well as hematopoietic stem cells. Therefore, we hypothesized that functional VEGF receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias. We demonstrate that certain leukemias not only produce VEGF but also express functional VEGFR-2 in vivo and in vitro, resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation. Approximately 50% of freshly isolated leukemias expressed mRNA and protein for VEGFR-2. VEGF165 induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF165 also induced the expression of MMP-9 by leukemic cells and promoted their migration through reconstituted basement membrane. The neutralizing mAb IMC-1C11, specific to human VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF165-mediated proliferation of leukemic cells and VEGF-induced leukemic cell migration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice. Interruption of signaling by VEGFRs, particularly VEGFR-2, may provide a novel strategy for inhibiting leukemic cell proliferation.
PMCID: PMC380247  PMID: 10953026

Results 1-23 (23)