Strong correlation between VEGF and MCL-1 mRNA expression levels in B-cell chronic lymphocytic leukemia.

Expression of the anti-apoptotic myeloid cell leukemia-1 (MCL-1) gene is a novel prognostic factor in B-cell chronic lymphocytic leukemia (B-CLL). Vascular and endothelial growth factor (VEGF) and interleukin-6 (IL-6) are able to upregulate MCL-1 via autocrine signaling loops. In 88 B-CLL patients, we found a strong correlation of MCL-1 gene expression with VEGF (P<10(-7)) but not with IL-6 mRNA levels.

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.

Standardized criteria for diagnosis and response assessment are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Therefore, a National Cancer Institute-sponsored Working Group (NCI-WG) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for patients with CLL in 1988, which were updated in 1996. During the past decade, considerable progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options.

Trinucleotide repeat dynamic mutation identifying susceptibility in familial and sporadic chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) has a strong hereditary component, but an understanding of predisposition genes is poor. Anticipation with familial CLL has been reported, although the molecular mechanism is unknown. Expansion of trinucleotide repeat sequences underlies anticipation observed in neurodegenerative disease.

Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations.

The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased and characterized by the existence of subsets of cases with closely homologous ("stereotyped") complementarity-determining region 3 (CDR3) sequences. In the present series, 201 (21.9%) of 916 patients with CLL expressed IGHV genes that belonged to 1 of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3.

CLL biology and prognosis.

Chronic lymphocytic leukemia (CLL) follows an extremely variable course with survival ranging from months to decades. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in CLL patients. In particular, the mutational profile of Ig genes and some cytogenetic abnormalities have been found to be important predictors of prognosis in CLL.

Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia.

Recently, considerable progress has been made in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with chronic lymphocytic leukemia (CLL) or detect minimal residual disease after therapy. These developments have created uncertainty for clinicians who hope to incorporate the use of these markers and new disease-assessment tools into standard clinical practice. However, clinical trials are required to determine whether poor-prognosis leukemia-cell markers, such as expression of unmutated immunoglobulin genes or the zeta-associated protein of 70 kDa (ZAP-70), can be used as the basis for determining the time or type of therapy.

Familial cancer associated with a polymorphism in ARLTS1.

Background: The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene.

Methods: We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant.

Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the mu and CD79a chains.

Low levels of B-cell-receptor (BCR) expression are the hallmark of tumoral B lymphocytes in B-cell chronic lymphocytic leukemia (B-CLL). These cells also respond inadequately to stimulation through the BCR. This receptor consists of a surface immunoglobulin associated with a CD79a/CD79b heterodimer.

Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells.

Activation-induced cytidine deaminase (AID) is key to initiating somatic hypermutation (SHM) and class switch recombination (CSR), but its mode of action and regulation remains unclear. Since Pax-5 and Id-2 transcription factors play an opposing role in AID regulation, we have studied the expression of Pax-5, Id-2, and prdm-1 genes in 54 chronic lymphocytic leukemia (CLL) B cells. In 21 cases, presence of AID is constantly associated with high expression of the complete form of the Pax-5 gene (Pax-5a) and lower expression of the Id-2 and prdm-1 transcripts.

Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene.

We studied immunoglobulin variable heavy-chain (IGHV) repertoire and mutational status in 553 patients with chronic lymphocytic leukemia (CLL) from the Mediterranean area to gain insight into the potential pathogenetic role of antigenic stimulation. The most commonly represented IGHV genes mirrored the usage of normal B cells, with the exception of IGHV1-18, IGHV3-30.3, and IGHV4-59 that were underrepresented.

Perspectives in chronic lymphocytic leukemia biology and management.

Considerable progress has been achieved in the comprehension of the pathogenesis, prognosis, assessment, and treatment of chronic lymphocytic leukemia. However, this progress also has introduced new enigmas in the fields of biology, prognosis, and treatment. This article discusses some unanswered questions in these different topics.

Somatic mutations can lead to a loss of superantigenic and polyreactive binding.

Although antibodies have been assumed to bind a specific antigen, evidence exists showing that a single antibody can bind to multiple unrelated antigens. We previously studied a human monoclonal antibody expressing a mutated form of the V(H)3-73 gene and displaying anti-tubulin activity in a patient suffering from an immunocytic lymphoma. Despite its expression of a V(H)3 family member, this immunoglobulin failed to react with protein A (SpA), suggesting that somatic mutations could account for its change in specificity.

[Cell therapy by dendritic cells in chronic lymphoid leukemia: state of the art].

Chronic lymphocytic leukemia (CLL) results from the accumulation of small mature, slowly dividing, monoclonal B lymphocytes. The clinical course of this disease is heterogeneous, with some patients progressing rapidly with early death whilst others exhibit a more stable, possibly, non-progressing disease lasting many years. Despite progress in therapy, relapse invariably occurs and the disease remains uncurable.

Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia.

Purpose: Rai's and Binet's staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet's classification in 145 patients.

[Autoantibodies, tolerance and autoimmunity].

In 1900, the group from Metchnikoff suggested the concept of autoimmunization by demonstrating the presence of autoantibodies in normal conditions; which was opposed to the concept of horror autotoxicus raised by Ehrlich. Landsteiner's description of the transfusion compatibility rules and 50 year-later work from Burnett's and Medawar's groups lead to the clonal deletion theory as a general explanation of tolerance and autoimmunity. However, more recent work succeeded demonstrating that autoreactive B cells constitute a substantial part of the B-cell repertoire and that this autoreactive repertoire secretes the so-called natural autoantibodies (NAA) characterized by their broad reactivity mainly directed against very well conserved public epitopes.

Monocyte-derived dendritic cells in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) results from the accumulation of small mature, slowly dividing, monoclonal B lymphocytes. The clinical course of this disease is heterogeneous, with some patients progressing rapidly with early death whilst others exhibit a more stable, possibly, non-progressing disease lasting many years. Despite progress in therapy, relapse invariably occurs and the disease remains incurable.

[Chronic lymphoid leukemia: a single disease or 2 distinct diseases?].

Chronic Lymphocytic Leukemia (CLL) most commonly arises from a malignant clone of B cells with a characteristic phenotype, an autoreactive activity and an increased resistance to apoptosis. It is far from uniform in presentation and clinical course. About one-third of patients never require treatment and have a long survival; in another third an initial indolent phase is followed by progression of the disease; the remaining third of patients have aggressive disease at the outset and need immediate treatment.

Idiotype-pulsed dendritic cells are able to induce antitumoral cytotoxic CD8 cells in chronic lymphocytic leukaemia.

Idiotypic structures of immunoglobulins from malignant B cells constitute tumour-specific antigens, though the function of immunoglobulin-specific CD8+ T cells in disease control and rejection remains unclear. We have studied five cases of B chronic lymphocytic leukaemia patients affected with indolent (three patients) or aggressive (two patients) disease. We showed that CD8+ T cells with major histocompatibility complex class I-restricted cytotoxicity against autologous tumour B cells could be generated following repeated stimulations with idiotype-pulsed dendritic cells in vitro.

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation.

In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch mu DNA region, CSR, and the SHM in 65 CLL patients.

High occurence of DRB1 11 in chronic lymphocytic leukaemia families.

Recently, linkage analysis of a series of familial chronic lymphocytic leukaemia (CLL) showed that affected sibling pairs did not share common major histocompatibilty complex haplotypes. We analysed Class I and II antigens in 11 Italian families with familial CLL. Although there was no association of disease status with any particular human leucocyte antigen, there was an overrepresentation of DRB1 11 alleles in these families (P = 0.

Defective assembly of the B-cell receptor chains accounts for its low expression in B-chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (B-CLL) characteristically displays low amounts of B-cell receptor (BCR), which mainly consists of the heterodimer CD79a/CD79b bound non-covalently with the surface immunoglobulin (SIg). This heterodimer is required for SIg expression and BCR signalling. To better define the mechanisms related to low BCR expression, we have investigated transcription, protein synthesis, assembly and transport of the BCR in B-CLL cells.

Transgenic B lymphocytes expressing a human cold agglutinin escape tolerance following experimental infection of mice by Mycoplasma pulmonis.

Several microbial infections, including Mycoplasma pneumoniae respiratory infection, are capable, in man, of transiently inducing the expression of anti-red blood cell autoantibody called cold agglutinins (CA). To analyze the mechanisms by which immune tolerance is broken following a mycoplasma infection, we used transgenic mice expressing a pathogenic human CA, designated CA-GAS, specific for sialylated carbohydrates. In these mice peripheral deletion of autoreactive B lymphocytes and receptor editing, prevent the development of autoimmune hemolytic anemia.