Molecular prognostic factors in diffuse large B-cell lymphoma.

The treatment of patients with diffuse large B-cell lymphoma (DLBCL) has been guided traditionally by clinical parameters such as the Ann Arbor Staging Classification for Hodgkin's disease. Although the International Prognostic Index (IPI) represents the most widely accepted prognostic model, there is still a marked variability in outcome within identical IPI subgroups, reflecting the heterogeneity of this malignancy. Use of DNA microarray, real-time reverse transcription polymerase chain reaction, and tissue array immunohistochemistry methodologies makes the development of new classifications possible based on molecular profiling.

Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation.

We identified the human germinal center-associated lymphoma (HGAL) in gene-expression profiling studies of diffuse large B-cell lymphoma (DLBCL). The expression of HGAL correlated with survival in patients with DLBCL. The HGAL gene is the human homolog of M17, a mouse gene expressed specifically in normal germinal center (GC) B cells.

Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphoma in South Florida and review of the literature.

The etiology of non-Hodgkin's lymphoma is unknown in the majority of the cases. Although Epstein-Barr virus, human T-cell leukemia-lymphoma virus and human herpes virus-8 have been established as casual agents in the pathogenesis of specific types of lymphoma, the role of hepatitis C virus (HCV) in lymphomagenesis remains controversial, with marked geographic variability. We conducted an epidemiologic study to evaluate the prevalence of hepatitis C virus infection in patients with lymphoma in South Florida.

Apoptosis-stimulating protein of p53-2 (ASPP2/53BP2L) is an E2F target gene.

The p53 pathway is a central apoptotic regulator. Deregulation of the Rb/E2F pathway occurs in a majority of tumors, resulting in both unrestrained proliferation and enhanced apoptosis sensitivity via p53-dependent and independent mechanisms. However, the mechanisms coupling the p53 and Rb/E2F pathways remain incompletely understood.

Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas.

Diffuse large B-cell lymphomas (DLBCLs) can be subclassified into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like tumors characterized by long and short survival, respectively. In contrast to ABC-like DLBCL, GCB-like tumors exhibit high expression of components of the interleukin 4 (IL-4) signaling pathway and of IL-4 target genes such as BCL6 and HGAL, whose high expression independently predicts better survival. These observations suggest distinct activity of the IL-4 signaling pathway in DLBCL subtypes.

AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity.

Activation-induced cytidine deaminase (AID), highly expressed in germinal center (GC)-lymphocytes, is involved in somatic hypermutation (SHM). We examined AID expression in diffuse large B-cell lymphomas (DLBCL) of germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes. These two types of DLBCL are characterized by high and low expression of GC-specific genes, respectively.

Somatostatin receptor scintigraphy in MALT lymphoma of the lacrimal gland treated with rituximab.

Non-gastric stage I extranodal marginal zone lymphomas of MALT are usually treated with local therapy. However, distant relapses in other extranodal sites are not uncommon suggesting under-staging of these patients using conventional image studies. Positron emission tomography (PET) scans are frequently negative in this subgroup of patients with lymphoma and therefore do not significantly contribute to the staging process.

Primary diffuse large cell lymphoma of the mandible.

Primary diffuse large cell lymphoma of the mandible is a rare form of extranodal non-Hodgkin's lymphoma (NHL). Herein we present 4 cases treated at our institution over a 5-year period and review 40 cases previously reported in the English-literature. The median age at presentation is 51 years with equal distribution between males and females.

Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes.

Background: Several gene-expression signatures can be used to predict the prognosis in diffuse large-B-cell lymphoma, but the lack of practical tests for a genome-scale analysis has restricted the use of this method.

Methods: We studied 36 genes whose expression had been reported to predict survival in diffuse large-B-cell lymphoma. We measured the expression of each of these genes in independent samples of lymphoma from 66 patients by quantitative real-time polymerase-chain-reaction analyses and related the results to overall survival.

Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions.

Higher grade histological transformation of follicular lymphoma (FL) to more aggressive diffuse large B-cell lymphomas (DLBCL) occurs in 10-60% of the cases. Review of the current knowledge of genetic and molecular alterations associated with the higher grade transformation of FCL suggests that the process that leads to clinically and phenotypically similar end-point can occur by functionally diverse genetic lesions. The most commonly identified genetic alterations associated with the FCL transformation are TP53 gene mutations, inactivation of CDKN2A and CDKN2B genes and deregulation of the C-MYC gene.

Analysis of FAS (CD95) gene mutations in higher-grade transformation of follicle center lymphoma.

The FAS antigen (CD95/APO-1) is suggested to be a tumor suppressor gene since mice and patients with congenital FAS mutations are prone to B cell lymphomas and somatic FAS mutations are described in hematological and solid tumors. Indeed, mutations of the FAS antigen have been found in 13% of multiple myelomas, 6% of follicle center lymphomas (FCL) and 21% of diffuse large B-cell lymphomas (DLBCL). To assess the possible role of FAS mutations in higher-grade transformation of FCL, biopsy specimens from 16 FCL patients were analyzed by denaturing high performance liquid chromatography and direct sequencing.

The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene.

The BCL6 gene, which functions as a transcription repressor, is the target of multiple chromosomal translocations in non-Hodgkin's lymphomas (NHL). These translocations occur in the nontranslated region of the BCL6 gene, juxtaposing regulatory sequences of the diverse partner genes to the open reading frame of the BCL6 gene and thus are thought to deregulate BCL6 gene expression. The levels of expression of the BCL6 gene and protein have been demonstrated to predict the clinical outcome of diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma: insights gained from gene expression profiling.

Analysis of global gene expression with DNA microarrays has great potential to improve the understanding of tumorigenesis advance tumor diagnosis and classification, and affect cancer treatment. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. However, we now realize that the disease is extremely heterogeneous.

BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma.

Follicular lymphoma (FL) is characterized by a relatively indolent clinical course, but the disease often transforms into a more aggressive large cell lymphoma with a rapidly progressive clinical course. In the present study, we analyzed 41 cases of FL known to have subsequently transformed to aggressive lymphoma and an additional 64 FL samples from patients not subsequently transformed. We studied BCL6 gene rearrangement by the methodology of long-distance inverse polymerase chain reaction (LDI-PCR).

Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies.

Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) is a powerful method for measurement of gene expression for diagnostic and prognostic studies of non-Hodgkin's lymphomas (NHL). In order for this technique to gain wide applicability, it is critically important to establish a uniform method for normalization of RNA input. In this study, we have determined the best method to quantify the RNA/cDNA input per reaction and searched for the most useful endogenous control genes for normalization of the measurements, based on their abundance and lowest variability between different types of lymphoid cells.

Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome.

ASPP2 interacts with the tumor suppressor protein p53, promotes damage-induced apoptosis, and can specifically stimulate p53 apoptotic function. Thus, ASPP2 may function as a tumor suppressor and/or play a role in the cellular response to cytotoxic injury. To explore the role of ASPP2 in human cancer, we determined ASPP2 expression in two lymphoma subtypes with differing clinical outcomes: diffuse large B-cell lymphoma (DLBCL) and follicular center lymphoma (FCL).

HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma.

We have cloned and characterized a novel human gene, HGAL (human germinal center-associated lymphoma), which predicts outcome in patients with diffuse large B-cell lymphoma (DLBCL). The HGAL gene comprises 6 exons and encodes a cytoplasmic protein of 178 amino acids that contains an immunoreceptor tyrosine-based activation motif (ITAM). It is highly expressed in germinal center (GC) lymphocytes and GC-derived lymphomas and is homologous to the mouse GC-specific gene M17.

Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations.

Genomic aberrations in a series of paired biopsy samples from patients who presented initially with follicle center lymphoma (FCL) and subsequently transformed to diffuse large B-cell lymphoma (DLBCL) were measured by array comparative genomic hybridization (CGH). The consequences of these aberrations on gene expression were determined by comparison with expression analysis on these specimens using cDNA microarrays. A heterogeneous pattern of acquired genomic abnormalities was observed upon transformation, some of which were recurrent in small subsets of patients.

BCL-6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the BCL-6 gene.

Follicle center lymphoma (FCL) is an indolent low-grade B cell non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive diffuse large B cell lymphoma (DLBCL). Histological transformation of FCL is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is commonly implicated in the pathogenesis of DLBCL and its expression may be altered by clonal rearrangements and somatic point mutations in its 5' non-translated regulatory region.

Cyclosporin A upmodulates bleomycin-induced pulmonary fibrosis in BALB/c mice.

Background: Intratracheal instillation of bleomycin (Bleo) into rodents serves as a model for human lung fibrosis. Various mouse strains respond differently to Bleo, and BALB/c mice are relatively resistant.

Objective: Since T lymphocytes have been shown to play a major role in this model, the effect of the immunomodulator cyclosporin A (CyA) on lung fibrosis was studied in Bleo-'resistant' BALB/c mice.

Mutation of the ATM gene is not involved in the pathogenesis of either follicle center lymphoma or its transformation to higher-grade lymphoma.

Loss of function of the ataxia-telangiectasia mutated (ATM) gene, located on human chromosome 11q22-23, is the cause of ataxia-telangiectasia (A-T), which is associated with an extremely high risk for lymphoma. Abnormalities in 11q22-23, including deletions and mutations of the ATM gene, have been reported in T-cell prolymphocytic leukemias, B-CLL and in mantle cell lymphoma. In a survey of gene expression in follicle center lymphomas (FCL) and diffuse large B-cell lymphomas (DLBCL), almost all FCL expressed significant levels of ATM and the majority of DLBCL expressed low levels of ATM.

Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes.

The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of the cases of histological transformation.