The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands.

In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling.

CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression.

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n = 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d+ subpopulation and a CD49d- subpopulation.

Cluster analysis of immunophenotypic data: the example of chronic lymphocytic leukemia.

Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have previously proposed an original method to identify the immunophenotypic signature of chronic lymphocytic leukemia (CLL) subsets with different prognosis, named surface-antigen expression profiling. According to this method, expression data for surface markers can be successfully analyzed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim to identify the immunophenotypic signature of CLL subsets with different prognosis.

An interactive diary for diet management (DAI): a new telemedicine system able to promote body weight reduction, nutritional education, and consumption of fresh local produce.

Background: The aim of this multicenter, longitudinal, single-arm, pre-post comparison was to test a telemedicine system able to promote body weight reduction, nutritional education, and consumption of fresh local produce.

Methods: DAI (MeTeDa srl, San Benedetto del Tronto, Italy) is a software for mobile phones to support patients following a specific dietetic program. It facilitates the communication between the patient and dietician via short text messages.

ZAP-70 expression in B-cell chronic lymphocytic leukemia: evaluation by external (isotypic) or internal (T/NK cells) controls and correlation with IgV(H) mutations.

Background: Expression of T cell specific zeta-associated protein 70 (ZAP-70) by B-cell chronic lymphocytic leukemia (B-CLL) cells, as investigated by flow cytometry, has both prognostic relevance and predictive power as surrogate for immunoglobulin heavy chain variable region (IgV(H)) mutations, although a standardization of the cytometric protocol is still lacking.

Methods: Flow cytometric analyses for ZAP-70 were performed in peripheral blood samples from 145 B-CLL (124 with IgV(H) mutations) by a standard three-color protocol. Identification of ZAP-70(+) cell population was based on an external negative control, i.

A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia.

We have previously identified 12 surface antigens whose differential expression represented the signature of B-cell chronic lymphocytic leukemia (B-CLL) subsets with different prognosis. In the present study, expression data for these antigens, as determined in 137 B-CLL cases, all with survivals, were utilized to devise a comprehensive immunophenotypic scoring system of prognostic relevance for B-CLL patients. In particular, univariate z score was employed to identify the markers with greater prognostic impact, while maximally selected log-rank statistics were chosen to define the optimal cut-off points capable to split patients into two groups with different survivals.

Mutational status of IgVH genes consistent with antigen-driven selection but not percent of mutations has prognostic impact in B-cell chronic lymphocytic leukemia.

Mutational status of immunoglobulin heavy-chain variable-region (IgVH) genes, along with CD38 expression, is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL). Configuration of IgVH genes displaying > 2% mismatch has been shown to correlate with longer survivals. In a series of 64 B-CLLs, we failed to confirm the prognostic value of the IgVH gene mutational status by using the suggested cutoff.

Methylation-regulated expression of cancer testis antigens in primary effusion lymphoma: immunotherapeutic implications.

Primary effusion lymphoma (PEL) is a large B-cell neoplasm with an unfavorable prognosis and limited therapeutic options. In this study, cancer testis antigens (CTA) were investigated as potential immunotherapeutic targets in patients with PEL. Baseline expression of a panel of 11 CTA was highly heterogeneous among five PEL cell lines.

Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery.

Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H) genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H) mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgV(H) gene per cent mutations above or below the 2% cut-off.

CD26 expression correlates with a reduced sensitivity to 2'-deoxycoformycin-induced growth inhibition and apoptosis in T-cell leukemia/lymphomas.

Purpose And Experimental Design: dCF (2'-deoxycoformycin) is a potent inhibitor of ADA (adenosine deaminase), an enzyme regulating intra- and extracellular concentrations of purine metabolites. ADA exists as cytosolic and extracellular forms, the latter colocalized on the cell surface with CD26. Once the surface expression of CD26 and ADA in a panel of cell lines and primary samples of T-cell leukemia/lymphoma was defined, we correlated this expression with the antiproliferative and apoptotic effect of dCF.

CD40L induces proliferation, self-renewal, rescue from apoptosis, and production of cytokines by CD40-expressing AML blasts.

Objective: Conflicting experimental and clinical results have been reported regarding the role of CD40 in acute myeloid leukemia (AML). In the present study, we analyzed the capability of CD40L/CD154 to modulate several functional aspects of CD40-expressing AML blasts.

Methods: After defining the constitutive expression levels of CD40 in a wide panel (n = 67) of AMLs and evaluating the capability of cytokines to modulate its expression, we investigated the effects of CD40 engagement by soluble (s) CD40L on proliferation, self-renewal capacity, apoptosis, homotypic adhesion, and cytokine production of leukemia cells.

Hodgkin and Reed-Sternberg cells express functional c-kit receptors and interact with primary fibroblasts from Hodgkin's disease-involved lymph nodes through soluble and membrane-bound stem cell factor.

Classic Hodgkin's disease (cHD) is a lymphoid neoplasia characterized by few malignant Hodgkin and Reed-Sternberg (H-RS) cells, embedded in an abundant background of non-tumour cells. We have previously demonstrated the expression in primary H-RS cells of the receptor tyrosine kinase (RTK) c-kit; here we describe its functional role in the cross-talk between H-RS cells themselves with neighbouring cell populations. In particular, we analysed the expression of c-kit and its ligand stem cell factor (SCF) in a panel of HD-derived cell lines and fibroblasts from HD-involved lymph nodes (HDF).

Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells.

The human interleukin-3 receptor (IL-3R) is a heterodimeric complex consisting of an IL-3-specific alpha chain (IL-3Ralpha) and a common beta chain (beta(c)), this latter shared with the receptors for granulocyte-macrophage colony-stimulating factor and IL-5. Despite extensive research on cytokine circuitries regulating proliferation and survival of tumor cells in Hodgkin's disease (HD) the functional expression of IL-3Rs in this pathobiological entity has not yet been investigated. In the present study, we demonstrate that the great majority (>90%) of malignant Hodgkin and Reed-Sternberg cells of classic HD (19 of 19 analyzed cases) express IL-3Ralpha by immunostaining of frozen sections and cell suspensions from involved lymph nodes.