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1.  The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-related Non-Hodgkin’s Lymphoma 
Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin’s lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with HLA-B* 08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in Caucasians most likely represents a true etiologic factor remains uncertain. We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. SNPs in LTA and TNF and in six other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A) and rs6467 (C)) were associated with AIDS-NHL (OR=2.7, 95% CI: 1.5–4.8, p=0.0009 and OR=3.2, 95% CI: 1.6–6.6 p=0.0008; respectively). These two haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.
doi:10.1097/QAI.0b013e3181b017d5
PMCID: PMC3015185  PMID: 19654554
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study
2.  B cell-stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B cell lymphoma 
Background
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Methods
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Results
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Conclusions
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Impact
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
doi:10.1158/1055-9965.EPI-11-0037
PMCID: PMC3132317  PMID: 21527584
lymphoma; B cell; cytokines; AIDS; immune activation
3.  Levels of Murine, but Not Human, CXCL13 Are Greatly Elevated in NOD-SCID Mice Bearing the AIDS-Associated Burkitt Lymphoma Cell Line, 2F7 
PLoS ONE  2013;8(8):e72414.
Currently, few rodent models of AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. CXCL13 is the ligand for CXCR5, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in ascites, as measured by ELISA. As shown by immunohistochemistry, murine CXCL13 was associated with macrophage-like tumor-infiltrating cells that appeared to be histiocytes. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may potentially identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL. These results also identify CXCL13 as a potential biomarker for this disease, which is consistent with previous studies showing that serum levels of CXCL13 were elevated in human subjects who developed AIDS-lymphoma. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the assessment of potential tumor biomarkers for this disease.
doi:10.1371/journal.pone.0072414
PMCID: PMC3732224  PMID: 23936541
4.  Assessment of Pre-Diagnosis Biomarkers of Immune Activation and Inflammation – Insights on the Etiology of Lymphoma 
Journal of proteome research  2010;10(1):113-119.
The DNA-modifying processes that are involved in B lymphocyte activation, somatic hypermutation (SHM) and IgH class switch recombination (CSR), have the potential to lead to genetic errors that lead to the genesis of B cell cancers, such as lymphoma. Given the potential contribution of these immune mechanisms to the development of cancer, assessment of the expression of cytokines and other immune stimulatory molecules that drive B cell activation, prior to lymphoma diagnosis, may provide insights into the etiology of these cancers. Here, we review studies that have examined pre-diagnosis protein biomarkers for non-Hodgkin lymphoma (NHL), both AIDS-related NHL, as well as NHL seen in immunocompetent populations. Overall, these studies provide support for the notion that B cell hyper-activation is elevated preceding the appearance of AIDS-NHL, particularly those forms of AIDS-NHL that are not driven by EBV infection, and which presumably arise from errors in IgH CSR and SHM. In more limited studies, it appears that dysregulation of cytokine production also precedes the diagnosis of NHL in HIV-negative persons. The availability of pre-diagnosis serum/plasma from cohort studies provides unique opportunities for proteomic approaches to identify novel pre-diagnosis etiologic biomarkers for NHL.
doi:10.1021/pr100729z
PMCID: PMC3017655  PMID: 20886858
5.  Expression and Function of the Chemokine, CXCL13, and Its Receptor, CXCR5, in Aids-Associated Non-Hodgkin's Lymphoma 
AIDS Research and Treatment  2010;2010:164586.
Background. The homeostatic chemokine, CXCL13 (BLC, BCA-1), helps direct the recirculation of mature, resting B cells, which express its receptor, CXCR5. CXCL13/CXCR5 are expressed, and may play a role, in some non-AIDS-associated B cell tumors. Objective. To determine if CXCL13/CXCR5 are associated with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Methods. Serum CXCL13 levels were measured by ELISA in 46 subjects who developed AIDS-NHL in the Multicenter AIDS Cohort Study and in controls. The expression or function of CXCL13 and CXCR5 was examined on primary AIDS-NHL specimens or AIDS-NHL cell lines. Results. Serum CXCL13 levels were significantly elevated in the AIDS-NHL group compared to controls. All primary AIDS-NHL specimens showed CXCR5 expression and most also showed CXCL13 expression. AIDS-NHL cell lines expressed CXCR5 and showed chemotaxis towards CXCL13. Conclusions. CXCL13/CXCR5 are expressed in AIDS-NHL and could potentially be involved in its biology. CXCL13 may have potential as a biomarker for AIDS-NHL.
doi:10.1155/2010/164586
PMCID: PMC3065842  PMID: 21490903
6.  Blockade of PI3K/AKT pathway enhances sensitivity of Raji cells to chemotherapy through down-regulation of HSP70 
Up-regulation of heat shock protein 70 (HSP70) could be elicited primarily by heat in former studies, and this was proved to be associated with cancer progression. Burkitt's lymphoma is one of highly aggressive B-cell non-Hodgkin’s lymphoma and is one of the fastest growing human tumors. To investigate the effect of HSP70 expression on the sensitivity of human Burkitt lymphoma cells (Raji cells) to chemotherapy and its role in the involvement of PI3K/AKT pathway, we evaluated the effects of LY294002, a PI3K inhibitor, on the expression of HSP70 and cell sensitivity to adriamycin (ADM) or cisplatin (DDP). In present study, expressions of HSP70, AKT and phosphorylated AKT (p-AKT) in Raji cells were measured by Western-Blot. Apoptosis index of Raji cells was examined by flow cytometry. Cytotoxicities of adriamycin (ADM) and cisplatin (DDP) were determined by WST-8 assay. We found that hyperthermia (42 degrees for 1 hour) up-regulated the expression of HSP70 expression and blockade of PI3K/AKT pathway down-regulated HSP70 expression in Raji cells. Compared to cells treated with ADM or DDP alone, hyperthermia protected cells from chemotherapy while LY294002 enhanced sensitivity of Raji cells to chemotherapy. Our results suggested down-regulation of HSP70 expression by blockade of PI3K/AKT pathway maybe responsible for the increased sensitivity of Raji cells to chemotherapy. Targeting PI3K/AKT pathway or inhibiting HSP70 expression may be beneficial for chemotherapy treatment of Burkitt lymphoma patients.
doi:10.1186/1475-2867-13-48
PMCID: PMC3680239  PMID: 23706027
Raji; Hyperthermia; HSP70; PI3K/AKT
7.  Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection 
Current opinion in oncology  2012;24(5):531-536.
Purpose of review
To estimate the impact of highly effective antiretroviral therapy (ART) on the incidence and prognosis of Hodgkin lymphoma among people with human immunodeficiency virus infection or AIDS (PWHA).
Recent findings
Age-adjusted incidence of Hodgkin lymphoma in PWHA is unchanged and is still five-fold to fifteen-fold higher than in the general population. Aging of the PWHA population with ART may account for increasing numbers of Hodgkin lymphoma cases. CD4 cell count has a complex relationship to Hodgkin lymphoma risk in PWHA. Depending on the time of measurement, Hodgkin lymphoma risk is highest with 50–249 CD4cells/µl, and falling CD4 count on ART may be a harbinger of Hodgkin lymphoma onset. HIV load appears irrelevant to Hodgkin lymphoma. For obscure reasons, Hodgkin lymphoma risk may be elevated soon after starting ART, but the risk is probably modestly reduced with 6 or more months on ART. For PWHA who develop Hodgkin lymphoma, ART and ABVD chemotherapy can be administered safely, with one recent study demonstrating equivalent outcomes for HIV-positive and HIV-negative Hodgkin lymphoma patients.
Summary
Vigilance for Hodgkin lymphoma is needed for immune-deficient PWHA, including those on ART. ART with opportunistic infection prophylaxis enables the delivery of effective chemotherapy for Hodgkin lymphoma, leading to a good prognosis.
doi:10.1097/CCO.0b013e3283560697
PMCID: PMC3604881  PMID: 22729154
acquired immunodeficiency syndrome; antiretroviral therapy; cancer chemotherapy; CD4 count; Hodgkin lymphoma; human immunodeficiency virus
8.  Development of non-Hodgkin’s lymphoma in a patient with primary biliary cirrhosis: A case report and review of the literature 
Patients with autoimmune disorders seem to have an elevated risk of lymphoma, especially non-Hodgkin’s lymphoma (NHL). The increased risk has been attributed to the disturbance of immune function found in these patients or to the immunosuppressive therapy used to treat the autoimmune disorders. However, little information exists about the estimated baseline risk for lymphoma in patients with primary biliary cirrhosis (PBC). In this case report, we describe a female patient who developed nodal diffuse large B-cell lymphoma ten years following PBC diagnosis. Twenty five additional case reports (19 NHL and 4 Hodgkin’s disease (HD), 2 without data about NHL or Hodgkin’s disease) predominantly females were identified in the English literature. B-cell lymphoma was the most common NHL type reported but beyond that no clear predisposition for any specific lymphoma subtype was documented. PBC usually preceded lymphoma diagnosis. Fifteen cases had extranodal localization and the most common site was the liver.
PMCID: PMC3959296  PMID: 24713720
PBC; non-Hodgkin’s lymphoma; autoimmune disorders
9.  Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1 
PLoS ONE  2011;6(11):e26949.
Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.
doi:10.1371/journal.pone.0026949
PMCID: PMC3212525  PMID: 22096508
10.  Circulating Serum Free Light Chains As Predictive Markers of AIDS-Related Lymphoma 
Journal of Clinical Oncology  2010;28(5):773-779.
Purpose
HIV-infected persons have an elevated risk of developing non-Hodgkin's lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals.
Patients and Methods
By using three cohorts of HIV-infected persons (from 1982 to 2005), we identified 66 individuals who developed NHL and 225 matched (by cohort, sex, ethnicity, age, and CD4 count), HIV-infected, lymphoma-free controls who had available stored prediagnostic blood samples. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years before diagnosis/selection were assayed for IgG, IgM, and IgA levels; monoclonal (M) Igs; and κ and λ free light chain (FLC) levels. Patients and matched controls were compared by using conditional logistic regression.
Results
The κ and λ FLCs were both significantly higher in patients (eg, in 2- to 5-year window: median κ, 4.24 v 3.43 mg/dL; median λ, 4.04 v 3.09 mg/dL) and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection (eg, NHL risk 3.76-fold higher with κ concentration at least 2.00 times the upper limit of normal, and 8.13-fold higher with λ concentration at least 2.00 times the upper limit of normal compared with normal levels). In contrast, IgG, IgM, and IgA levels were similar in patients and controls. M proteins were detected in only two patients with NHL (3%) and in nine controls (4%), and they were not significantly associated with NHL risk.
Conclusion
Elevated FLCs may represent sensitive markers of polyclonal B-cell activation and dysfunction and could be useful for identifying HIV-infected persons at increased NHL risk.
doi:10.1200/JCO.2009.25.1322
PMCID: PMC2834393  PMID: 20048176
11.  Hepatitis C Virus-Related Lymphomagenesis in a Mouse Model 
ISRN Hematology  2011;2011:167501.
B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes.
doi:10.5402/2011/167501
PMCID: PMC3195281  PMID: 22084693
12.  Abdominal Manifestations of Lymphoma: Spectrum of Imaging Features 
ISRN Radiology  2013;2013:483069.
Non-Hodgkin and Hodgkin lymphomas frequently involve many structures in the abdomen and pelvis. Extranodal disease is more common with Non-Hodgkin's lymphoma than with Hodgkin's lymphoma. Though it may be part of a systemic lymphoma, single onset of nodal lymphoma is not rare. Extranodal lymphoma has been described in virtually every organ and tissue. In decreasing order of frequency, the spleen, liver, gastrointestinal tract, pancreas, abdominal wall, genitourinary tract, adrenal, peritoneal cavity, and biliary tract are involved. The purpose of this review is to discuss and illustrate the spectrum of appearances of nodal and extranodal lymphomas, including AIDS-related lymphomas, in the abdominopelvic region using a multimodality approach, especially cross-sectional imaging techniques. The most common radiologic patterns of involvement are illustrated. Familiarity with the imaging manifestations that are diagnostically specific for lymphoma is important because imaging plays an important role in the noninvasive management of disease.
doi:10.5402/2013/483069
PMCID: PMC4045537  PMID: 24967280
13.  HLA-DR (Ia) immune phenotype predicts outcome for patients with diffuse large cell lymphoma. 
Journal of Clinical Investigation  1988;82(1):370-372.
The clinical utility for establishing the immune phenotype in patients with non-Hodgkin's lymphoma is controversial. To help resolve this dilemma, we studied 104 consecutive patients with diffuse large cell lymphoma, the most common subtype of potentially curable non-Hodgkin's lymphomas. The presence or absence of the human class II histocompatibility antigen was determined using the monoclonal antibody anti-HLA-DR (Ia), and the results correlated with pretreatment clinical features and survival. We found that eight HLA-DR negative patients had similar pretreatment clinical characteristics compared with 96 HLA-DR positive patients, but HLA-DR negative patients had a significantly shorter survival duration compared with HLA-DR positive patients (P = 0.003 log-rank). The median survival of the HLA-DR negative patients was 0.5 years compared to 2.8 yr for the HLA-DR positive patients. No HLA-DR negative patient survived beyond 1.5 yr. A multi-variate analysis, adjusting for prognostic factors of known clinical significance, confirmed the importance of HLA-DR as a prognostic factor (P = 0.016). We conclude that determining the presence of HLA-DR is a relatively simple pretreatment study that identifies a small but important group of patients who are not curable using currently available combination chemotherapy.
PMCID: PMC303519  PMID: 3392214
14.  Role of Hsp90 in Systemic Lupus Erythematosus and Its Clinical Relevance 
Autoimmune Diseases  2012;2012:728605.
Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins which play an essential role as molecular chaperones in protein folding and transport. Heat Shock Protein 90 (Hsp90) is not mandatory for the biogenesis of most proteins, rather it participate in structural maturation and conformational regulation of a number of signaling molecules and transcription factors. Hsp90 has been shown to play an important role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Dysregulated expression of Type I interferon α, activation of B cells and production of autoantibodies are hallmarks of SLE. The enhanced levels of Hsp90 were detected in the serum of SLE patients. The elevated level of Hsp90 in SLE has also been correlated with increased levels of IL-6 and presence of autoantibodies to Hsp90. This suggests that Hsp90 may contribute to the inflammation and disease progression and that targeting of Hsp 90 expression may be a potential treatment of SLE. The pharmacologic inhibition of Hsp90 was successfully applied in mouse models of autoimmune encephalomyelitis and SLE—like autoimmune diseases. Thus targeting Hsp90 may be an effective treatment for SLE, especially if combined with other targeted therapeutic approaches.
doi:10.1155/2012/728605
PMCID: PMC3471389  PMID: 23091704
15.  Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma 
PLoS ONE  2014;9(6):e99144.
Background
Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation.
Methods
This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays.
Results
A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers.
Conclusions
These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.
doi:10.1371/journal.pone.0099144
PMCID: PMC4055650  PMID: 24922518
16.  Diverse Hematological Malignancies Including Hodgkin-Like Lymphomas Develop in Chimeric MHC Class II Transgenic Mice 
PLoS ONE  2009;4(12):e8539.
A chimeric HLA-DR4-H2-E (DR4) homozygous transgenic mouse line spontaneously develops diverse hematological malignancies with high frequency (70%). The majority of malignancies were distributed equally between T and B cell neoplasms and included lymphoblastic T cell lymphoma (LTCL), lymphoblastic B cell lymphoma (LBCL), diffuse large B cell lymphoma (DLBCL), the histiocyte/T cell rich variant of DLBCL (DLBCL-HA/T cell rich DLBCL), splenic marginal zone lymphoma (SMZL), follicular B cell lymphoma (FBL) and plasmacytoma (PCT). Most of these neoplasms were highly similar to human diseases. Also, some non-lymphoid malignancies such as acute myeloid leukemia (AML) and histiocytic sarcoma were found. Interestingly, composite lymphomas, including Hodgkin-like lymphomas, were also detected that had CD30+ Hodgkin/Reed-Sternberg (H/RS)-like cells, representing a tumor type not previously described in mice. Analysis of microdissected H/RS-like cells revealed their origin as germinal center B cells bearing somatic hypermutations and, in some instances, crippled mutations, as described for human Hodgkin lymphoma (HL). Transgene integration in an oncogene was excluded as an exclusive driving force of tumorigenesis and age-related lymphoma development suggests a multi-step process. Thus, this DR4 line is a useful model to investigate common molecular mechanisms that may contribute to important neoplastic diseases in man.
doi:10.1371/journal.pone.0008539
PMCID: PMC2796171  PMID: 20046882
17.  Soluble HLA Revisited 
Leukemia research  2006;31(2):121-125.
The goal of this editorial is to revisit soluble human leukocyte antigens (sHLA) and to highlight the findings reported by Albitar et al. in this issue on the relation between sHLA levels in Non-Hodgkin’s Lymphoma (NHL) and Hodgkin’s Disease (HD). We will review key aspects of sHLA including soluble HLA-G, which has received a lot of attention in recent publications. We will then address the role of sHLA in lymphoproliferative diseases and in solid organ tumors. Lastly, we will comment on the results of Albitar et al. and their relevance to clinical application in NHL.
doi:10.1016/j.leukres.2006.06.008
PMCID: PMC1876709  PMID: 16860865
soluble human leukocyte antigen; non-Hodgkin’s Lymphoma; graft monitoring; immune modulation
18.  Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia 
Cell Stress & Chaperones  2001;6(4):316-325.
Heat shock proteins (Hsps) are ubiquitous proteins that are induced following exposure to sublethal heat shock, are highly conserved during evolution, and protect cells from damage through their function as molecular chaperones. Some cancers demonstrate elevated levels of Hsp70, and their expression has been associated with cell proliferation, disease prognosis, and resistance to chemotherapy. In this study, we developed a tetracycline-regulated gene expression system to determine the specific effects of inducible Hsp70 on cell growth and protection against hyperthermia in MCF-7 breast cancer cells. MCF-7 cells expressing high levels of Hsp70 demonstrated a significantly faster doubling time (39 hours) compared with nonoverexpressing control cells (54 hours). The effect of elevated Hsp70 on cell proliferation was characterized further by 5-bromo-2′deoxyuridine labeling, which demonstrated a higher number of second and third division metaphases in cells at 42 and 69 hours, respectively. Estimates based on cell cycle analysis and mean doubling time indicated that Hsp70 may be exerting its growth-stimulating effect on MCF-7 cells primarily by shortening of the G0/G1 and S phases of the cell cycle. In addition to the effects on cell growth, we found that elevated levels of Hsp70 were sufficient to confer a significant level of protection against heat in MCF-7 cells. The results of this study support existing evidence linking Hsp70 expression with cell growth and cytoprotection in human cancer cells.
PMCID: PMC434414  PMID: 11795468
19.  A human T cell lymphoma secreting an immunoglobulin E specific helper factor. 
Journal of Clinical Investigation  1985;75(6):1977-1982.
An 8-yr-old nonallergic girl with non-Hodgkin's lymphoma had markedly elevated serum IgE at presentation (greater than 10,000 IU/ml), negative skin tests to a battery of 24 common allergens, and no evidence of parasitic infestation. Serum levels of IgG, IgA, and IgM were normal. Remission after cytotoxic chemotherapy was accompanied by a marked reduction in serum IgE levels (to less than 200 IU/ml) with no change in the level of serum IgG, IgM, or IgA. Recurrence of the lymphoma 7 mo after remission was accompanied by an isotype specific rise in serum IgE (to 3,850 IU/ml). Isoelectric focusing revealed that the IgE was polyclonal. Phenotypic analysis of the lymphoma obtained during relapse revealed all (greater than 98%) cells to be T3+, T4+, and T8+. Incubation of lymphoma cells with human myeloma IgE followed by immunosorbent purified fluorescein tagged goat anti-human IgE (anti-IgE PS-adsorbed over IgE ADZ) stained 25% of the cells. In contrast, less than 1% of the cells were stained after incubation with human IgG followed by fluorescein conjugated goat anti-human IgE. Supernatants from lymphoma cells (5 X 10(6)/ml, 48 h) enhanced IgE production in B cells derived from four patients with allergic rhinitis (mean +/- SD picograms per milliliter of net IgE 930 +/- 320 in unstimulated cultures versus 2,450 +/- 650 in cultures stimulated with lymphoma supernatants; P less than 0.01) but did not induce IgE synthesis in B cells from two normal subjects that synthesized no IgE spontaneously. Lymphoma supernatants failed to enhance IgG synthesis by B cells of both allergic and nonallergic subjects. These results indicate that a T cell lymphoma comprised of cells bearing Fc receptors for IgE with a phenotype characteristic of immature T cells (i.e., T3+, T4+, T8+) exhibited IgE specific helper function. This lymphoma may represent the monoclonal expansion of a subpopulation of IgE specific helper T cells.
Images
PMCID: PMC425557  PMID: 3159754
20.  The Frequency and Clinical Relevance of Multidrug Resistance Protein Expression in Patients with Lymphoma 
Turkish Journal of Hematology  2012;29(2):120-129.
Objective: Multidrug resistance is a cause of treatment failure in patients with malignant lymphoma; however, the frequency and clinical relevance of multidrug resistance protein expression are unclear. The present study aimed to investigate expression of the most common multidrug resistance proteins in a group of lymphoma patients.
Material and Methods: The study included 44 previously untreated lymphoma patients (non-Hodgkin’s lymphoma [n = 21], non-malignant lymphadenopathy [n = 13], and Hodgkin’s lymphoma [n = 10]). MDR1, MRP, and LRP expression was assessed via quantitative PCR of lymph node biopsy specimens.
Results: In the non-Hodgkin’s lymphoma group MDR1 was positive in 23.8% (5/21) of the patients, MRP was positive in 57.14% (12/21), and LRP was positive in 90.47% (19/21). In the non-malignant lymphadenopathy group, MDR1 was positive in 46.15% (6/13) of the patients, MRP was positive in 84.61% (11/13), and LRP was positive in 100% (13/13). In the Hodgkin’s lymphoma group MDR1 was positive in 50% (5/10) of the patients, MRP was positive in 50% (5/10), and LRP was positive in 80% (8/10). MDR1, MRP, and LRP expression did not differ between the 3 groups. Furthermore, MDR1, MRP, and LRP expression wasn’t associated with tumor stage, response to first-line therapy, the erythrocyte sedimentation rate, or C reactive protein, beta 2 microglobulin, serum lactate dehydrogenase, and albumin levels. Additionally, survival time in the MDR1- and MRP-positive, and MDR1- and MRP-negative patients did not differ (comparison of LRP was not possible due to the small number of LRP-negative patients).
Conclusion: According to the present findings, future studies should investigate alternative pathways of multidrug resistance in order to arrive at a better understanding of treatment failure in lymphoma patients.
doi:10.5505/tjh.2012.60362
PMCID: PMC3986949  PMID: 24744642
Multidrug resistance; non-Hodgkin’s lymphoma; Hodgkin’s lymphoma; Survival
21.  Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise 
Current pharmaceutical design  2008;14(21):2051-2060.
There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.
PMCID: PMC2745246  PMID: 18691115
22.  DNA binding of heat shock factor to the heat shock element is insufficient for transcriptional activation in murine erythroleukemia cells. 
Molecular and Cellular Biology  1990;10(4):1600-1608.
The heat shock response is among the most highly conserved examples of regulated gene expression, being present in all cellular organisms. Transcriptional activation of heat shock genes by increased temperature or other cellular stresses is mediated by the binding of a heat shock factor (HSF) to a conserved nucleotide sequence (the heat shock element) present in the promoter of heat-inducible genes. Despite the high degree of conservation of this response, embryonic stages of development are characterized by the absence of a heat shock response. Murine erythroleukemia (MEL) cells also lack this response, and we report here a detailed characterization of this defect for one of the most highly conserved of these genes, hsp70. Surprisingly, heat-induced transcriptional activation of this gene does not occur, despite the induction of a protein with the binding specificity of murine HSF. However, the MEL HSF differs slightly in apparent size from the HSF in 3T3 cells, which exhibit a normal heat shock response. These data suggest that activation of mammalian HSF by heat requires at least two separate steps: an alteration of binding activity followed by further modification that activates transcription. MEL cells do not respond to heat shock because they lack the ability to perform this secondary modification. These cells provide a useful system for characterizing heat shock activation in mammals.
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PMCID: PMC362265  PMID: 2320006
23.  HIV-1 Tat mimetic of VEGF correlates with increased microvessels density in AIDS-related diffuse large B-cell and Burkitt lymphomas 
Journal of Hematopathology  2008;1(1):3-10.
Angiogenic switch marks the beginning of tumor’s strategy to acquire independent blood supply. In some subtypes of non-Hodgkin’s lymphomas, higher local vascular endothelial growth factor (VEGF) expression correlates with increased microvessel density. However, this local VEGF expression is higher only in tumors with elevated expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. Several studies have indicated that VEGF receptors are also targeted by Tat protein from the HIV-1-infected cells. Given the similarity of the basic region of Tat to the angiogenic factors (basic fibroblast growth factor, VEGF), Tat mimics these proteins and binds to their receptors. We evaluated the role of HIV-1 Tat in regulating the level of VEGF expression and microvessel density in the AIDS-related diffuse large B-cell (DLBCL) and Burkitt lymphomas (BL). By luciferase assay, we showed that VEGF promoter activity was downregulated in vitro in cells transfected with Tat. Reduced VEGF protein expression in primary HIV-1 positive BL and DLBCL, compared to the negative cases, supported the findings of promoter downregulation from the cell lines. Microvascular density assessed by CD34 expression was, however, higher in HIV-1 positive than in HIV-1 negative tumors. These results suggest that Tat has a wider angiogenic role, besides the regulation of VEGF expression. Thus, targeting Tat protein itself and stabilizing transient silencing of VEGF expression or use of monoclonal antibodies against their receptors in the AIDS-associated tumors will open a window for future explorable pathways in the management of angiogenic phenotypes in the AIDS-associated non-Hodgkin’s lymphomas.
doi:10.1007/s12308-008-0002-z
PMCID: PMC2712328  PMID: 19669199
HIV-1 Tat; Microvessel density; Diffuse large B-cell; Burkitt lymphoma
24.  Association of heat shock proteins with all-cause mortality 
Age  2012;35(4):1367-1376.
Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9417-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9417-7
PMCID: PMC3705092  PMID: 22555621
Heat shock proteins; HEAT shock factor 2; All-cause mortality
25.  Ataxia telangiectasia gene mutations in leukaemia and lymphoma 
Journal of Clinical Pathology  2001;54(7):512-516.
Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22–23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22–23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.
Key Words: lymphoid malignancy • mutation • ataxia telangiectasia gene
doi:10.1136/jcp.54.7.512
PMCID: PMC1731462  PMID: 11429421

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