Transient monoclonal expansion of CD8+/CD57+ T-cell large granular lymphocytes after primary cytomegalovirus infection.

Lymphocytosis associated with viral infection is generally polyclonal or oligoclonal. In this article, we describe a case of transient monoclonal CD8+/CD57+ T-cell lymphocytosis with large granular lymphocyte (LGL) morphology occurring after primary CMV infection and review cases of virus-associated monoclonal CD8+ T-cell expansions reported in the literature. Several clinical features shared by virus-associated monoclonal CD8+ T-cell expansions suggest the reactive nature of the lymphocytosis.

Prevalence and clinical characteristics of immune thrombocytopenic purpura in a cohort of monoclonal gammopathy of uncertain significance.

Monoclonal gammopathy of uncertain significance (MGUS) may become symptomatic for autoimmune manifestations. We report on the prevalence and clinical course of immune thrombocytopenic purpura (ITP) observed in a consecutive series of 228 MGUS patients. At MGUS diagnosis, ITP was determined in 6/228 cases, accounting for a prevalence of 2630/100 000 [95% confidence interval (CI): 1210-5620].

Similarities and differences between the light and heavy chain Ig variable region gene repertoires in chronic lymphocytic leukemia.

Analyses of Ig V(H)DJ(H) rearrangements expressed by B-CLL cells have provided insights into the antigen receptor repertoire of B-CLL cells and the maturation stages of B-lymphocytes that give rise to this disease. However, less information is available about the L chain V gene segments utilized by B-CLL cells and to what extent their characteristics resemble those of the H chain. We analyzed the V(L) and J(L) gene segments of 206 B-CLL patients, paying particular attention to frequency of use and association, mutation status, and LCDR3 characteristics.

Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas.

Despite recent improvements in treatment, a significant fraction of patients with diffuse large B-cell lymphoma (DLBCL) still fail therapy. Therefore, new therapeutic modalities are needed to advance the cure rate. Seliciclib (CYC202, R-roscovitine) is a purine analog developed as an inhibitor of CDK2/cyclin E CDK7/cyclin H and CDK9/cyclin T.

Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study.

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy.

Simultaneous diagnosis of CD3+ T-cell large granular lymphocyte leukaemia and true thymic hyperplasia.

CD3+ T-cell large granular lymphocyte (LGL) leukaemia is a mature T-cell neoplasm of cytotoxic T-lymphocytes. Neutropenia represents the most frequent peripheral blood cytopenia associated with CD3+ T-cell LGL leukaemia. A wide variety of diseases associated with LGL leukaemia have been reported, both autoimmune and neoplastic.

B-cell posttransplant lymphoproliferative disorders in heart and/or lungs recipients: clinical and molecular-histogenetic study of 17 cases from a single institution.

Background: Posttransplantation lymphoproliferative disorders (PTLDs) are heterogeneous lymphoid proliferations representing a major complication of solid organ transplant. This study details the clinicopathological and molecular features of 17 B-cell PTLDs observed in a single center series of 988 heart and/or lung transplant recipients.

Methods: Cases were classified according to World Health Organization lymphoma classification and tested for Epstein-Barr Virus (EBV), clonality, histogenetic phenotypic (CD10, Bcl-6, MUM1, CD138), and genotypic (immunoglobulin and BCL-6 genes somatic hypermutation) markers.

Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma.

The molecular mechanisms involved in histologic transformation of follicular lymphoma (FL) and B-chronic lymphocytic leukemia (B-CLL) to diffuse large B-cell lymphoma (DLBCL) are heterogeneous and largely unknown. Here we explored whether aberrant somatic hypermutation, leading to the acquisition of new mutations in PIM-1, PAX-5, RhoH/TTF and c-MYC genes, is involved in transformation from FL or B-CLL to DLBCL. Eighteen sequential pairs of FL/DLBCL (n=9) and B-CLL/DLBCL (n=9) were investigated.

Hairy cell leukaemia complicated by anti-MAG paraproteinemic demyelinating neuropathy: resolution of neurological syndrome after cladribrine treatment.

Hairy cell leukaemia (HCL) occasionally displays a monoclonal gammopathy, yet the association of HCL with paraproteinemic demyelinating neuropathy (PDN) has not been reported. We describe a HCL case complicated by PDN and high titers of monoclonal IgM against myelin associated glycoprotein (MAG). Heavy and light chains of the patient's anti-MAG monoclonal protein were consistent with those expressed by HCL cells.

Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.

Comparative genome-wide profiling of post-transplant lymphoproliferative disorders and diffuse large B-cell lymphomas.

Post-transplant lymphoproliferative disorders (PTLD) are a major complication of solid organ transplantation, representing a cause of severe morbidity and mortality. Apart from Epstein-Barr virus infection, knowledge of the pathogenesis of monoclonal PTLD is limited. Powerful analysis techniques, such as whole genomic DNA profiling (array comparative genomic hybridisation), can improve our understanding of PTLD pathogenesis.

Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas.

Objective: The aim of this study was to determine the occurrence of polymorphic variants of EBV BamHI fragment Z (BZLF1) promoter zone Zp in tumor and non-tumor-associated EBV. We characterized the Zp region in type A and type B EBV, infecting AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and non-malignant lymphoid tissues derived from HIV-positive patients and from healthy individuals.

Methods: The Zp region was directly sequenced in 133 EBV-positive DNA samples: 63 AIDS-NHL (32 systemic AIDS-NHL and 31 AIDS-primary central nervous system lymphoma [AIDS-PCNSL]), 30 lymphoid tissues derived from HIV-positive individuals and 40 lymphoid samples derived from healthy individuals.

Usefulness of JAK2V617F mutation in distinguishing idiopathic erythrocytosis from polycythemia vera.

Idiopathic erythrocytosis (IE) is a primary erythrocytosis not fulfilling the criteria for polycythemia vera (PV) diagnosis. In order to verify the relationship between IE and PV, we screened JAK2V617F mutation in a consecutive series of 11 IE and, for comparison, in 15 PV. JAK2V617F mutation was screened by both cDNA sequencing and mutation specific PCR in both peripheral blood and bone marrow samples.

Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma.

Aberrant somatic hypermutation (SHM) has been identified as a mechanism for genomewide instability in diffuse large B-cell lymphoma (DLBCL). To assess whether aberrant SHM plays a role in the molecular pathogenesis of Hodgkin lymphoma (HL), we investigated microdissected neoplastic cells of nodular lymphocyte-predominant HL (NLPHL; n = 10) and classic HL (cHL; n = 9) for the presence of mutations in the 5' sequences of 4 previously identified aberrant SHM targets (PIM1, PAX5, RhoH/TTF, c-MYC). Mutations in one or more genes were detected in 80% of NLPHLs and 55% of cHLs, with 50% and 30% of patients carrying mutations in 2 or more genes, respectively.

Splenic marginal zone lymphoma: a prognostic model for clinical use.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .

Immunophenotypic characterization of IgVH3-72 B-cell chronic lymphocytic leukaemia (B-CLL).

The frequent expression of the otherwise rare IgVH3-72 gene was demonstrated in highly stable B-cell chronic lymphocytic leukaemias (B-CLLs). Here we describe the immunophenotypic profiles of eleven IgVH3-72 B-CLLs, by investigating expression of ZAP-70 and of a set of surface antigens previously demonstrated to represent the signature of distinct B-CLL prognostic groups. All IgVH3-72 B-CLLs revealed a homogeneous immunophenotypic profile, expressing all the markers associated with good prognosis, but not those representing the signature of bad prognosis B-CLLs, including ZAP-70.

Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.

Among B-cell lymphomas mantle cell lymphoma (MCL) has the worst prognosis. By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we analysed 26 MCL samples to identify genes relevant to MCL pathogenesis and that could represent new therapeutic targets. Recurrent genomic deletions and gains were detected.

Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis.

Post-transplant lymphoproliferative disorders (PTLD) represent a serious complication of solid organ and allogeneic bone marrow transplantation. PTLD generally display B-cell lineage derivation, involvement of extranodal sites, aggressive histology and clinical behaviour, and frequent association with EBV infection. The occurrence of IgV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV-positive and EBV-negative cases.

KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects. Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotype.

Background: Kaposi sarcoma associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) associated lymphomas, which often develop in human immunodeficiency virus (HIV) infected patients with advanced AIDS, present predominantly as primary effusion lymphoma (PEL) or, less frequently, as "solid" extracavitary based lymphomas, associated with serous effusions. These last lymphomas, also called "solid PEL", have been reported before the development of an effusion lymphoma and after resolution of PEL. Interestingly, KSHV/HHV-8 associated lymphomas that present as solid or extracavitary based lesions in HIV seropositive patients without serous effusions have been reported recently.

Downregulation of the major histocompatibility complex class I molecules by human herpesvirus type 8 and impaired natural killer cell activity in primary effusion lymphoma development.

Primary effusion lymphomas (PELs) are invariably infected by human herpesvirus type 8 (HHV8) and often co-infected by Epstein-Barr virus (EBV). We found that expression of major histocompatibility complex class I (MHC-I) surface molecules was significantly decreased in PEL cells when compared with HHV8 negative lymphomas, irrespective of EBV infection. MHC-I downregulation rendered PEL cells sensitive to recognition and killing by natural killer (NK) cells.

Analysis of aberrant somatic hypermutation (SHM) in non-Hodgkin's lymphomas of patients with chronic HCV infection.

Hepatitis C virus (HCV) and aberrant somatic hypermutation (SHM) have each been suggested to contribute to the development of B-cell non-Hodgkin's lymphoma (NHL). The incidence of PIM-1, PAX-5, RhoH/TTF, and c-MYC mutations in tumour biopsy specimens from 32 HCV-infected B-cell NHL patients was analysed to determine whether the extent of aberrant SHM among these patients differed from that previously reported for HCV-negative B-cell NHL patients. Mutation of PIM-1, PAX-5, RhoH/TTF, and c-MYC was detected in 4 (13%), 5 (16%), 4 (13%), and 4 (13%) of 32 samples, respectively.