Pathogenesis Of non-Hodgkin Lymphoma Research Articles

Frequency distribution of hepatitis C infection among patients with B-cell non-Hodgkin lymphoma in underserved minority population.

e18536 Background: The role of hepatitis C Virus (HCV) infection in the pathogenesis of non-Hodgkin lymphoma is not well clarified. Several studies show a variation (0% to 37%) in the prevalence of HCV infection in B-cell Non-Hodgkin Lymphoma (B-NHL) by geographical location. Mucosal-associated lymphoid tissue lymphoma (MALT) and diffuse large B-cell lymphoma (DLBCL) were reported to have the highest prevalence of HCV infection in subtype specific analysis of B-NHL in previous studies. Methods: We retrospectively studied 112 patients with histological diagnosis of B-NHL confirmed by flow cytometry and immunohistochemistry, consecutively seen from 2002 to 2007.Their clinical features and outcomes were evaluated. Results: Histopatholgy in patients with HCV was as follows: 12(67%) DLBCL, 3(16%) marginal zone lymphoma (MZL), 3(16%) Burkitt lymphoma (BL). 14(78%) patients had Stage III or IV disease, 11 (60%) had an IPI of ≥3, and 4(22%) had disease relapse. Regarding AA patients with HCV and B-NHL, the median age at diagnosis was 50 years, 6(60%) were males and 4 (40%) females. 8(80%) patients had DLBCL, 1(10%) had BL, and 1(10%) had MZL. 9 out of 10 had aggressive disease (DLBCL and BL). Conclusions: The prevalence of HCV infection in patients with B-NHL we presente is higher than previously reported in some U.S. studies. 83% of patients with B-NHL / HCV infection, and 90% of AA with B-NHL/HCV, had aggressive disease, which is significantly higher than previously reported. This linkage should be further studied, and its relationship to other healthcare disparities in underserved populations should be evaluated. Of 112 patients, 18 (16%) were HCV positive, 17 (15%) were HIV positive and 6(5%) were hepatitis B (HBV) positive. Among HCV positive patients, the median age at diagnosis was 48 years; 12 (67%) were males and 6 (33%) females. 10 (55%) were African American (AA), 4 (22%) Caucasian, 3 (16%) Hispanic and 1 (5%) was Asian. 1 (5%) patient had coinfection with HBV and 2 (11%) had coinfection with HIV. Race/ethnicity All patients HCV patients Caucasian 20 4 AA 50 10 Hispanic 35 3 Asian 5 1 Middle Eastern 2 0 Total 112 18 All types of B-NHL DLBCL MZL BL HCV patients 18 12 (67%) 3 (16%) 3 (16%)

Proapoptotic signaling activity of the anti-CD40 monoclonal antibody dacetuzumab circumvents multiple oncogenic transformation events and chemosensitizes NHL cells

Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The objective of this study was to elucidate the signal transduction-based antitumor mechanism(s) of action for the anti-CD40 monoclonal antibody dacetuzumab (SGN-40) in NHL. We report that dacetuzumab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuzumab-mediated CD40 signaling constitutively activated the nuclear factor-κB and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. In a second mechanism, dacetuzumab signaling induced the expression of the proapoptotic p53 family member TAp63α and downstream proteins associated with the intrinsic and extrinsic apoptotic machinery. Dacetuzumab was synergistic in combination with DNA-damaging chemotherapeutic drugs, correlating with TAp63α upregulation. Furthermore, dacetuzumab augmented the activity of rituximab in combination with multiple chemotherapies in the xenograft models of NHL. The ability of dacetuzumab signaling to circumvent oncogenic events and potentiate the activity of chemotherapy regimens provides a unique therapeutic approach to NHL.

Malignancies and Outcome in Patients with Ataxia-Telangiectasia: Results From the French National Registry for Primary Immune Deficiencies.

Abstract 1101Poster Board I-123 BackgroundAtaxia-Telangiectasia (A-T) is rare inherited condition characterized by progressive neurological impairment, oculocutaneous telangiectasias, susceptibility to infections and predisposition to cancer. A-T is due to bi-allelic mutations in the ATM gene located on chromosome 11q23. ATM encodes a multifunction serine-threonine kinase involved detection and repair of DNA double-strand breaks, and regulation of cell-cycle check-points and apoptosis. A-T patients present an increased susceptibility to antimitotic chemotherapy and radiation.. Cancer is a major contributor to morbidity and mortality in A-T and ATM mutation analysis suggests a correlation between the presence of bi-allelic loss-of–function mutations and earlier onset of cancer, mainly hematological malignancies (R. Micol et al., manuscript submitted). Here we analyze the prevalence, histological subtype and outcome in A-T patients presenting with malignancies. MethodsTwo-hundred and fifty A-T patients born between 1954 and 2005 and included in the registry held by the French National Reference Center for Primary Immune Deficiencies (CEREDIH, manuscript submitted) were retrospectively analyzed. Clinical and histological data was extracted from the CEREDIH database. ResultsFifty-five patients (22% of the entire A-T cohort) presented with malignancies. Mean age at diagnosis of malignancy was 14.4 years (SD 9.8). Forty-nine patients (89%) presented with hematological malignancies and 6 (10.9%) with adenocarcinoma (3 mammary gland, 2 gastric, 1 thyroid). Hematological malignancies occurred earlier than carcinomas (mean 11.8 vs. 33.7 years respectively, p<001). High-grade Non-hodgkin lymphoma (NHL) was the most frequent hematological malignancy (31 patients, 56.3%) followed by Hodgkin's lymphoma (HL, 9 cases, 16.3%), acute lymphoblastic leukemia (ALL, 7 cases, 12,7%) and T-cell prolymphocytic leukaemia (T-PLL, 2 cases, 3.6%). Among NHL, 20 were of B-cell phenotype, including 4 cases of Burkitt's lymphoma. Three NHL were of T-cell phenotype and in 8 cases the phenotype was not available. Information on tumor staging was available for 18 NHL. Seventeen NHL were disseminated (Ann Arbor stage III/IV). Extranodal involvement was present in 14 NHL, absent in one case and unknown in 16. Six NHL (all B-cell) were EBV(+), 2 EBV(-) and in 23 cases the information was missing. Thirteen out of 14 NHL patients for whom treatment information was available received chemotherapy. Information on dosage was available for 11 patients. Five of them received a reduced dose. Three patients with ALL received chemotherapy including 1 who also received radiotherapy as part of conditioning for allogeneic HSCT. Of the 3 patients with carcinoma for whom information was available, 1 received chemotherapy only, one radiotherapy only and one both. Toxicity was recorded for 8 NHL patients (no toxicity in 2, hematological in 2, other in 4). Treatment response was recorded in 9 NHL patients (CR in 3, PR in 3 and no response in 3). Cause of death was recorded in 10 NHL patients: 7 patients died from tumor progression, 1 from infection and 2 from other causes. Mean survival after diagnosis of malignancy was 1.3 years for all histological subtypes. Comparison according to type of response to treatment showed that patients undergoing a major response had a longer survival than patients with minor or no response (mean survival 4.14 years for the former vs. 0.28 years for the latter, p<0.05). DiscussionMalignancy is a major contributor to morbidity and mortality in A-T, occurring in 22% of the present cohort. Hematological malignancies, mainly high grade B-cell NHL, are the most frequent cancers observed (56.3% of the observed malignancies and 12.4% of the patients in the cohort). EBV is associated with a noticeable proportion of high grade B-cell lymphomas, implying a possible contribution of the underlying immune deficiency in the pathogenesis of NHL during A-T. Tolerance to treatment including radiotherapy is variable. Despite poor overall survival, several patients underwent prolonged remissions and experienced improved survival. These results underscore the need to treat A-T patients with malignancies providing proper supportive care, including prevention and treatment of infections and mucositis. Further analysis of ATM mutations is required to determine if tolerance and response to treatment is correlated with the genotype. DisclosuresNo relevant conflicts of interest to declare.

The Role of Major Histocompatibility Complex Polymorphisms in the Incidence and Outcome of Non-Hodgkin Lymphoma

Major histocompatibility complex (MHC) genes are involved in various mechanisms of pathogenesis and immunoediting of non-Hodgkin ’ s lymphoma (NHL). MHC class III polymorphisms, located within tumor necrosis factor (TNF) family gene cluster, have diverse expression in normal individuals and lymphoma patients, and their expression depends on the allelic version. Certain HLA class I and II gene products are involved in the tumor peptide presentation and ligation of specific T-cell receptors (TCR). They are involved in NHL pathogenesis either directly or as a consequence of the linkage disequilibrium (LD) with causative genes. TNF polymorphic alleles and closely located nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor like 1 (NFKBIL1) may lead to up-regulation of nuclear factor kappa B (NFκB) and adverse outcome of certain subsets of diffuse large B-cell lymphomas. In addition, HLA class I ligation to the natural killer (NK)-cell immunoglobulin-like receptors (KIR) plays a critical role in immunosurveillance of the tumors, which may result in deterioration of NHL outcome, especially when the repertoire of MHC-KIR interaction is reduced. This review summarizes clinical data of MHC allele and haplotype polymorphisms and their pleiotropic or epistatic links to the pathogenesis of NHL. Keywords: Genetic polymorphism, major histocompatibility complex, Non-Hodgkin lymphoma, pathogenesis

Serum Adiponectin As a Predictor of Childhood Non-Hodgkin's Lymphoma: A Nationwide Case-Control Study

To our knowledge, this is the first study exploring the association of childhood non-Hodgkin's lymphoma (NHL) with serum adiponectin and leptin levels in a nationwide case-control series. In addition, expression of adiponectin receptors in NHL specimens was assessed, and the association between adipokines and childhood NHL survival and prognosis was examined. We studied 121 incident childhood (0 to 14 years) NHL cases registered in the Nationwide Registry for Childhood Hematological Malignancies (1996 to 2006) and an equal number of matched controls, for whom sociodemographic, lifestyle, prenatal characteristics, and fasting blood serums were collected. Serum adiponectin and leptin levels were determined. Immunohistochemisty for adiponectin receptors expression was performed on commercially available adult NHL specimens (n = 30) and in a subset of childhood NHL cases (n = 6) that were available. Summary statistics, multiple conditional logistic regression analyses, and survival analysis were performed. Higher serum adiponectin, but not leptin, levels were independently associated with childhood NHL (odds ratio, 1.82; 95% CI, 1.30 to 2.56), after adjusting for obesity and established risk factors. Higher adiponectin levels at diagnosis were positively associated with relapse and poor survival, but hormone levels did not differ among NHL subtypes. Adiponectin receptors 1 and 2 were present in 90% and 57% of adult samples and in 83% and 100% of childhood NHL samples, respectively. Elevated serum adiponectin, but not leptin, levels are independently associated with childhood NHL and poor prognosis. Adiponectin receptors are expressed in NHL, suggesting that adiponectin may represent not only a potential clinically significant diagnostic and prognostic marker but also a molecule that may be implicated in NHL pathogenesis.

New treatment options for the management of non-Hodgkin lymphoma

Although the outcome of patients with non-Hodgkin lymphoma (NHL) has, in general, improved significantly over years, treatment failure due to drug resistance remains a problem. Recently, the focus of drug development has shifted from conventional cytotoxic drugs to agents directed against specific molecular targets and immunotherapy. This has mainly been driven by advances in the understanding of the molecular pathogenesis of NHL. A large number of promising new agents are in preclinical and clinical development. The challenge for clinicians is how best to incorporate them into already existing treatment regimes. This review will highlight some recent clinical trials focussing on targeted small molecules and monoclonal antibodies in NHL.

CXCL12 rs1801157 polymorphism in patients with breast cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

Chemokines and their receptors regulate the trafficking of immune cells during their development, inflammation, and tissue repair. The single-nucleotide polymorphism (SNP) rs1801157 (previously known as CXCL12-A/ stromal cell-derived factor-1 (SDF1)-3'A) in CXCL12/SDF1 gene was assessed in breast cancer, Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL), since the chemokine CXCL12, previously known as SDF1, and its receptor CXCR4 regulate leukocyte trafficking and many essential biological processes, including tumor growth, angiogenesis, and metastasis of different types of tumors. Genotyping was performed by PCR-RFLP (polymerase chain reaction followed by restriction fragment length polymorphism) using a restriction enzyme HpaII cleavage. No significant difference was observed in genotype distribution between breast cancer patients (GG: 57.3%; GA: 39.8%; AA: 2.9%) and healthy female controls (GG: 62.9%; GA: 33%; AA: 4.1%) nor between HL patients (GG: 61.1%; GA:27.8%; AA: 11.1%) and healthy controls (GG: 65.6%; GA: 28.9%; AA: 5.5%), whereas a significant difference was observed in genotype distribution between NHL patients (GG: 51.4%; GA: 47.1%; AA: 1.5%) and healthy controls (GG: 65.6%; GA: 28.9%; AA: 5.5%). Further studies will be necessary to elucidate the cancer chemokine network. However, this study suggests that CXCL12 rs1801157 polymorphism may have important implications in the pathogenesis of NHL.

Polymorphisms in the Estrogen Receptor 1 and Vitamin C and Matrix Metalloproteinase Gene Families Are Associated with Susceptibility to Lymphoma

BackgroundNon-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms.Methodology/Principal Findings768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23–0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06–0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk.Conclusions/SignificanceOur findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation.

Type 2 Diabetes Mellitus and Risk of Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis

Type 2 diabetes mellitus is associated with altered immune function and chronic inflammation. Both of these immune conditions are implicated in the pathogenesis of non-Hodgkin lymphoma. The authors performed a systematic review to summarize findings from the current literature on the association between history of type 2 diabetes mellitus and risk of non-Hodgkin lymphoma. Ten case-control studies and three prospective cohort studies were included in this review. Meta-analysis found that a history of type 2 diabetes mellitus was positively associated with overall non-Hodgkin lymphoma risk. However, there was significant heterogeneity between studies. Study design was an important source of heterogeneity. The rate ratio between type 2 diabetes mellitus and non-Hodgkin lymphoma was found to be 1.18 (95% confidence interval: 0.99, 1.42) among case-control studies and 1.79 (95% confidence interval: 1.30, 2.47) among the prospective cohort studies. Weaknesses were identified in some of the included studies in the areas of case and control selection, measurement of covariates and non-Hodgkin lymphoma, and confounding control. Although a positive association between type 2 diabetes mellitus and risk of non-Hodgkin lymphoma was suggested, the evidence is inconclusive because of methodological limitations of the included case-control studies. More prospective studies with improved control of confounding are needed to confirm these findings.

Role of chromosome 1 pericentric heterochromatin (1q) in pathogenesis of myelodysplastic syndromes: Report of 2 new cases

Chromosome 1 pericentromeric heterochromatin (1q) has been shown to play an important role in the pathogenesis of non-Hodgkin lymphoma and multiple myeloma. Myelodysplastic syndrome (MDS) results from marrow failure in two or more cell lineages. Although trisomy 1q has been reported in MDS, it is usually present with additional common abnormalities such as trisomy 8, monosomy 5 or monosomy 7, leading to speculation that 1q abnormalities are mostly secondary events representing clonal evolution. We report two cases of MDS in which consistent involvement of 1q heterochromatin is seen as the primary clonal abnormality. Both patients presented with fatigue and pancytopenia. Based on the published reports and our cases, we propose that the 1q heterochromatin plays a vital role in the pathophysiology of MDS. Abnormalities involving 1q result in aberrant heterochromatin/euchromatin junctions, leading to gene dosage abnormalities. Further studies of 1q abnormalities in MDS might provide specific insights as to the exact role of the excess 1q heterochromatin in the etiology of MDS.

Polymorphisms of Thymidylate Synthase in the 5′- and 3′-Untranslated Regions Associated with Risk of Non-Hodgkin's Lymphoma.

Thymidylate synthase (TS) catalyzes the conversion of dUMP by 5,10-methylenetetrahydrofolate to dTMP in DNA synthesis. Polymorphisms in the untranslated regions(UTRs) of TS, which may modulate TS transcription and expression, have been associated with susceptibility to several malignancies. In this study, to evaluate the association with TS the 28-bp tandem repeat(2R→3R) and the 6-bp deletion(6 bp-) and susceptibility to non-Hodgkin's lymphoma(NHL), large-scale population-based case-control study was conducted in Chonnam National University Hospital between Mar 1997 and Feb 2006. 553 patients with histologically comfirmed lymphoma and 1,324 controls were evaluated. The cases consisted of 275 diffuse large B-cell lymphomas (DLBCL), 109 T-cell lymphomas and 169 unclassifiable lymphomas. TS 2R2R genotype was significantly associated with increased risk for NHL and T-cell lymphoma, but not for DLBCL. Using subjects with the TS 3R3R as a reference group, the OR of TS 2R2R was 2.00 (95% CI 1.21–3.31, p=0.007) for NHL and 3.30 (95% CI 1.52–7.17, p=0.003) for T-cell lymphoma. The association was 1.65 fold higher and more evident for T-cell lymphoma than NHL. However, there was no significant association of TS 6bp- with NHL.In conclusion, theses results suggest that TS (2R→3R) may play an important role in the pathogenesis of NHL, and that DNA synthesis may play a crucial roles in the pathogenesis of specific NHL subtypes.

Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut

Several hereditary syndromes characterized by defective DNA repair are associated with high risk of non-Hodgkin lymphoma (NHL). To explore whether common polymorphisms in DNA repair genes affect risk of NHL in the general population, we evaluated the association between single nucleotide polymorphisms (SNPs) in DNA repair genes and risk of NHL in a population-based case-control study among women in Connecticut. A total of 518 NHL cases and 597 controls recruited into the study provided a biologic sample. Thirty-two SNPs in 18 genes involved in several DNA repair pathways were genotyped. Genotype data were analyzed by unconditional logistic regression adjusting for age and race. SNPs in four genes (ERCC5, ERCC2, WRN, and BRCA1) were associated with altered risk of NHL and diffuse large B-cell lymphoma (DLBCL), the major B cell subtype. In particular, ERCC5 Asp1104His was associated with increased risk of NHL overall (OR: 1.46; 95% CI: 1.13-1.88; P=0.004), DLBCL (OR: 1.44; 95% CI: 0.99-2.09; P=0.058), and also T cell lymphoma. WRN Cys1367Arg was associated with decreased risk of NHL overall (OR: 0.71; 95% CI: 0.56-0.91; P=0.007) and DLBCL (OR: 0.66; 95% CI: 0.45-0.95; P=0.024), as well as follicular and marginal zone lymphomas. Genetic polymorphisms in DNA repair genes, particularly ERCC5 and WRN, may play a role in the pathogenesis of NHL, especially for DLBCL. Further work is needed to extend these findings by carrying out extended haplotype analyses of these and related genes and to replicate the observations in other studies.

Methylenetetrahydrofolate Reductase and Methionine Synthase Polymorphism and Risk of Non-Hodgkin's Lymphoma.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are key enzymes in folate metabolism, which is essential for DNA methylation and synthesis. It is known that polymorphisms in its genes have been associated with some forms of cancer including lymphoma. Previous studies have shown MTHFR 677TT was associated with decreased risk of non-Hodgkin's lymphoma(NHL). However, recent two reports have shown MTHFR 677TT was associated with increased risk. To evaluate the association between the MTHFR C677T and MTR A2756G polymorphisms and risk of non-Hodgkin's lymphoma, large-scale population-based case-control study was conducted in Chonnam University Hwasun Hospital between March 1997 and June 2005. Three hundreds sixty-five patients with histologically comfirmed lymphoma and 1,162 controls were evaluated. Genotyping was done using PCR-RFLP. The cases consisted of 203 diffuse large B-cell lymphomas(DLBCL), 77 T-cell lymphomas, 62 other B-cell lymphomas, and 23 unclassifiable lymphomas. The MTHFR 677CT and 677TT genotypes were inversely associated with NHL and DLBCL, respectively. Using subjects with the MTHFR 677CC as reference group, the odds ratio of MTHFR 677CT and 677TT were (0.70, 95% CI 0.54–0.90) and (0.46, 95% CI 0.32–0.68) for NHL. The association was more evident for DLBCL (OR 0.56, 95% CI 0.40–0.78 for 677CT; OR 0.40, 95% CI 0.24–0.65 for 677TT). Dose-response effect was evident for the MTHFR T-allele (p < 0.01). There was no significant association of MTR A2756G with NHL. These results suggest that the MTHFR polymorphism may play an important role in the pathogenesis of NHL, particularly DLBCL.

Genome-Wide Analysis of Copy Number Alterations/LOH/Allelic Imbalances in Non-Hodgkin Lymphoma Using Ultrahigh-Density SNP-Genotyping Microarrays with the Robust CNAG Algorithms.

Non-Hodgkin lymphomas (NHL) are hematopoietic malignancies originated from diversity of peripheral lymphoid organs. During the past two decades, there have been significant advances in the pathogenesis of NHL including identification of a number of genes associated with the disease-specific translocations and other genetic alterations. In view of cytogenetics, however, NHL frequently shows complex chromosomal abnormalities involving copy number alterations as well as other unbalanced translocations, many of which have not been unveiled at the molecular levels.Affymetrix® 100K/500K mapping arrays were originally developed for large-scale SNP typing required for genome-wide association studies, but the quantitative nature of the whole-genome amplification and hybridization used in these platforms also makes them powerful tools for genome-wide analysis of cancer genomes with use of uniformly distributed 116,204/520,000 SNP-specific probes. Moreover the use of SNP specific probes enables allele-specific copy number analysis that is totally impossible with other platforms. Here we developed the robust algorithms (Copy number analyzer for Affymetrix® GeneChip®; CNAG) for high-quality processing of 100K/500K data and analyzed a total of 72 NHL samples (61 primary samples including 34 diffuse large B-cell lymphoma, 18 follicular lymphoma and 11 cell lines including 3 adult T cell leukemia/ lymphoma) for genome-wide copy number alterations, LOH, and allelic imbalances at the resolutions of 23.6/5.4 kb.In 100K analysis, 34 homozygous deletions and 42 high-grade amplifications and other numerous copy number alternations and/or LOH, were identified together with possible gene targets as for some regions. 500K analysis disclosed even more subtle changes. Common overlapping alternations included deletions in 1p31.1 and 9p21.3, and 19p13.32 and high-grade amplifications in 3p14.2–p14.1,7q21.13–q21.3, and 20q11.21.Of particular importance is, however, the finding of otherwise undetected copy number neutral LOHs, which are revealed only by allele-specific copy-number analysis. In fact the copy number neutral LOHs represented a novel type of genetic abnormality in NHL because they were very frequent and found in more than 87% (20/23) of NHL cases examined with allele-specific copy number analysis, making a stark contrast to ALL, in which these abnormalities were rare. They typically involved chromosomal ends, indicating somatic recombinations are the potential mechanism of generating these abnormalities. Notably, there was a clear predisposition of the copy number neutral LOH to specific chromosomal loci including 1p, 1q, 6p, 9p, 17q, and 19p suggesting existence of relevant genes to NHL pathogenesis within these common regions.In conclusion, Affymetrix® SNP-genotyping microarrays and our CNAG algorithms provide a powerful platform of dissecting NHL genomes and could facilitate identification of the novel molecular mechanisms for lymphomagenesis.

AIDS‐related non‐Hodgkin's lymphomas

This work reviews the current status of non-Hodgkin's lymphoma (NHL) in HIV infected patients. HIV infection remains at significantly increased risk for the development of NHL. The great majority of these lymphomas are high-grade monoclonal B-cell neoplasms often occurring in unusual sites. A number of genetic abnormalities have been found but additional studies are necessary to understand the etiology and pathogenesis of NHL in the setting of HIV infection. The cases in this paper have been seen on the Hematopathology service of the Tulane Health Sciences Center.

Possible involvement of neutrophils in a serum level increase of hepatocyte growth factor in non-Hodgkin's lymphoma

Serum levels of hepatocyte growth factor (HGF), a potent angiogenic factor, increase during various haematological malignancies. In this study, we examined serum HGF in 59 patients with non-Hodgkin's lymphoma (NHL). Serum HGF levels in NHL patients were increased, as were levels in patients with multiple myeloma, chronic myeloproliferative disorders, and myelodysplastic syndrome. Some 29 patients with T-cell lymphoma, including 20 with adult T-cell leukemia/lymphoma, exhibited a significant increase in serum HGF, as did 23 with B-cell lymphoma. The levels of serum HGF correlated with increased neutrophil counts (r=0.487, p<0.0001), and also paralleled a neutrophil increase in NHL patients who received granulocyte-colony stimulating factor (G-CSF) at the nadir of neutrophil count following chemotherapy. Additionally, in in vitro experiments, HGF secretion from polymorphonuclear neutrophils and its expression in bone marrow myeloid cells were stimulated by G-CSF. Although HGF has been thought to be involved in the pathogenesis of NHL through its angiogenic activities, these results suggest that HGF production by neutrophils and myeloid lineage cells may also contribute to an increase in serum HGF in NHL patients.

Genetic Association of Non Hodgkin's Lymphoma Susceptibility to Polymorphisms in the CTLA-4 Gene on Chromosome 2q33.

The current knowledge of potential risk factors for lymphomas is limited. There is strong evidence that altered immunological function entails an increased risk of lymphoma. CTLA-4 gene encodes for a receptor that provides a negative signal to the T-cell once an immune response is initiated and complete. It is located in the 2q33 chromosomal region that harbours several genes such as CD28, ICOS, all related to immune activation playing a pivotal role in T-lymphocyte activation. Polymorphisms in these genes have been associated to a number of autoimmune diseases, including blood disorders. We have recently reported that a functional polymorphism in the CTLA-4 gene is associated with Non-Hodgkin's lymphoma (NHL) and may have a role in genetic susceptibility to the disease.Since CD28, CTLA-4 and ICOS are closely linked and have related functions, aim of the present study was to extend the genetic analysis to the 2q33 chromosomal region harbouring these genes.Three polymorphisms of CTLA-4 gene (at positions -308C*T, +49A*G, +642 3′UTR (AT)n), the CD28 (CAA)n, ICOS c1564T*C and D2S72 markers within a 1.3cM region were analyzed in 100 unrelated NHL patients and in 128 healthy controls both originating from the central part of Sardinia. Statistical analysis was performed to test association of each marker with NHL using Chi-squared test and Odds Ratio (OR). Haplotypes were inferred and analyzed using the PHASE 2.1 software. Exact test of Linkage Disequilibrium (LD) was calculated between all pairs of seven markers separately in cases and controls using the Arlequin program.We found a strong association of the CTLA-4 +49*A and the 3′UTR (AT)82 alleles with NHL with ORs of 2 (CI95% 1.2–3.2) and 1.6 (CI95% 1.1–2.4), respectively. The −308*C−+49*A− (AT)82 was the most represented haplotype in the studied population and resulted associated with NHL (p value = 0.0029; OR = 1.7 [CI95% 1.2–2.5]). No independent association between CD28, ICOS and D2S72 markers was observed. Genetic analysis of the entire haplotype CD28–CTLA-4-D2S72-ICOS resulted in 196 and 234 different best haplotypes in patients and controls, respectively. The most common haplotype was CD28*163-308*C-+49*A-(AT)82-D2S72*156-ICOS*T and it was found to be significantly over-represented in NHLs than in controls (p value = 0.012, OR=1.86 CI95% 1.1–3). Strong LD was observed between the three CTLA-4 gene markers and the two adjacent markers CD28 and D2S72, and less significant LD was found between ICOS and some of the CTLA-4 gene markers. We found genetic linkage between a specific haplotype in the 2q33 region and NHL, but allelic association was detected for CTLA-4 markers and for none of the adjacent functionally related gene markers. Thus, it seems possible to dissect the CTLA-4 as the true “causative” risk gene for NHL susceptibility at least in Sardinian patients.The functional characterization of disease-associated CTLA4 gene variants will be worthy of future investigation to elucidate their role in the pathogenesis of NHL.

The Prevalence of Hepatitis C and Hepatitis G Virus Infection in Patients with B Cell Non-Hodgkin Lymphomas in Greece: A Hellenic Cooperative Oncology Group Study

Our aim was to investigate the association between chronic hepatitis C virus (HCV) infection and B cell non-Hodgkin lymphoma (NHL) in the Greek population. We studied 120 patients (70 men and 50 women, mean age 59 years) diagnosed with NHL. One hundred and eight had B cell NHL (90%) and 12 had T cell NHL (10%). The presence of anti-HCV antibodies in patients and controls was investigated using the monoclonal enzymatic immunoassay (MEIA) method. The detection of HCV RNA and hepatitis G virus (HGV) RNA in patients with B cell NHL and anti-HCV-positive controls was performed using an RT-PCR technique. Anti-HCV antibodies were present in only 2 of the 108 patients with B cell NHL (1.9%), while the prevalence of HCV infection in the healthy population was 0.6%, and in patients with various solid tumors treated with chemotherapy, it was 0.99%. Ten of the 108 B cell NHL patients (9.26%) were diagnosed as HGV RNA positive, while the prevalence of HGV infection in 285 Greek blood donors was 0.7%. Our findings do not confirm a strong association between HCV infection and B cell NHL for Greek patients. The increased prevalence of HGV infection detected in patients with NHL could imply the potential participation of HGV in the pathogenesis of NHL.

Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway

B lymphomagenesis is an uncontrolled expansion of immature precursors that fail to complete their differentiation program. This failure could be at least partly explained by inappropriate expression of several oncogenic transcription factors, such as Pax5 and Myc. Both Pax5 and c-Myc are implicated in the pathogenesis of non-Hodgkin lymphomas. To address their role in lymphomagenesis, we analyzed B-cell lymphomas derived from p53-null bone marrow progenitors infected in vivo by a Myc-encoding retrovirus. All Myc-induced lymphomas invariably maintained expression of Pax5, which is thought to be incompatible with terminal differentiation. However, upon culturing in vitro, several cell lines spontaneously down-regulated Pax5 and its target genes CD19, N-Myc, and MB1. Unexpectedly, other B-cell markers (eg, CD45R) were also down-regulated, and markers of myeloid lineage (CD11b and F4/80 antigen) were acquired instead. Moreover, cells assumed the morphology reminiscent of myeloid cells. A pool of F4/80-positive cells as well as several single-cell clones were obtained and reinjected into syngeneic mice. Remarkably, pooled cells rapidly re-expressed Pax5 and formed tumors of relatively mature lymphoid phenotype, with surface immunoglobulins being abundantly expressed. Approximately half of tumorigenic single-cell clones also abandoned myeloid differentiation and gave rise to B lymphomas. However, when secondary lymphoma cells were returned to in vitro conditions, they once again switched to myeloid differentiation. This process could be curbed via enforced expression of retrovirally encoded Pax5. Our data demonstrate that some Myc target cells are bipotent B-lymphoid/myeloid progenitors with the astonishing capacity to undergo successive rounds of lineage switching.

Mutations and molecular variants of the NBS1 gene in non-Hodgkin lymphoma.

Non-Hodgkin lymphomas (NHLs) are characterized by chromosomal translocations that juxtapose loci encoding lymphoid antigen receptors with cellular proto-oncogenes. These translocations are thought to arise from inaccurate processing of DNA breaks created during physiologic recombination of the antigen receptor genes in lymphocytes. The inherited disorders ataxia-telangiectasia and Nijmegen breakage syndrome are caused by mutations in the ATM and NBS1 genes, respectively, and are characterized by generalized genomic instability and a high incidence of lymphoid cancers. Lymphoid cells from patients with either disorder frequently have chromosomal translocations involving T-cell-receptor or immunoglobulin loci. To investigate the potential role of the NBS1 gene in the pathogenesis of NHL, we screened tumor DNA samples from 91 sporadic cases of NHL and genomic DNA from 154 control individuals for mutations in all 16 exons of the NBS1 gene and in flanking intronic sequences. One NHL case with a truncating mutation in NBS1 and a second NHL case with a putative missense mutation were detected. Neither mutation was observed among controls. Three additional putative missense mutations were observed only in the normal control samples. A panel of six common polymorphisms spanning the NBS1 gene was genotyped and provided no evidence for loss of heterozygosity in the NHL cases with mutations or in the NHL population overall. These results suggest that mutations in NBS1 do not play a major role in the development of NHL in the United States.