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Zoltan Matrai

Publications and source records attributed to Zoltan Matrai.

5 recordsLinked to original sources
PubMed2005

B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease in which interaction of the malignant cells with antigen is thought to play a key role. Individual CLL-cell clones markedly differ in their ability to respond to B-cell receptor ligation, but the mechanism underlying the frequent hyporesponsiveness is incompletely understood. Our aim was to further clarify the extent and cause of the B-cell receptor signaling abnormality in CLL and to assign pathophysiologic relevance to the presence or absence of B-cell receptor responsiveness. We show that extracellular signal-regulated kinase-2 phosphorylation, intracellular Ca2+ increases, CD79a phosphorylation, and translocation of the B-cell receptor to lipid rafts in response to ligation with anti-immunoglobulin M (as a surrogate for antigen) are features of CLL cells with relatively unmutated VH genes (<5% deviation from germ line) and a poor prognosis. B-cell receptor stimulation in these cases also promoted cell survival. In clones with mutated VH genes (>5% deviation from germ line), surface immunoglobulin M ligation failed to induce receptor translocation to rafts or to prolong cell survival. This failure of receptor translocation observed in mutated CLL cells was associated with the constitutive exclusion of the B-cell receptor from rafts by a mechanism involving src-dependent interactions between the B-cell receptor and the actin cytoskeleton. We conclude that exposure to antigen promotes the survival of unmutated CLL clones, contributing to the poor prognosis of this group. In contrast, hyporesponsive mutated CLL clones may have developed into a stage where continuous exposure to antigen results in relative tolerance to antigenic stimulation mediated by the exclusion of the B-cell receptor from lipid rafts.

Antigens, CD↗
PubMed2005

CD38 as a prognostic marker in CLL.

Cell-surface expression of CD38 in CLL has been recognised recently as a marker of progressive disease and poor outcome. In contrast to traditional staging systems, CD38 is able to identify progressive cases at an early stage. Measurement of CD38, in conjunction with other novel prognostic factors such as p53 and ZAP-70 helps to identify patients who might benefit from early and more intensive therapy. In addition, CD38 positivity can predict unmutated IgVH gene mutation status in most cases. These features, together with its easy applicability, render CD38 a valuable tool in the routine diagnostics of CLL. Questions remaining to be clarified about CD38 include the incidence and significance of its variations during the course of the disease, the optimal method to define CD38 positivity and the impact of different methodologies on results. Only after these issues are resolved can the definitive place of CD38 be defined in the diagnostics of CLL.

ADP-ribosyl Cyclase↗
PubMed2003

Correlation between cell size and CD38 expression in chronic lymphocytic leukaemia.

Both CD38 expression and increased cell size are features of B-lymphocyte activation and have been implicated as adverse prognostic factors in B-cell chronic lymphocytic leukaemia (CLL). We therefore examined the relationship between these two variables by FACS analysis in 140 consecutive CLL patients. Using the mean forward-angle light scatter (FSC) as a measure of cell size, circulating B lymphocytes were found to be significantly larger in "CD38-positive" cases (those in which the antigen was expressed in at least 20% of the malignant cells) as compared with "CD38-negative" patients (p = 0.029). Furthermore, within individual cases B lymphocytes expressing CD38 were, on average, significantly larger than cells that did not express the antigen (p < 0.0001). Finally, when B lymphocytes of individual "CD38-positive" cases were arbitrarily divided into large and small subpopulations using their mean FSC as a cut-off, CD38 was found to be more frequently expressed on the larger cells (p < 0.0001). This strong positive correlation between CD38 expression and cell size implicates cell activation as a possible underlying determinant of both tumour-cell phenotype and clinical outcome in CLL.

ADP-ribosyl Cyclase↗
PubMed2002

Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia.

Established adverse prognostic factors in chronic lymphocytic leukemia (CLL) include CD38 expression, relative lack of IgV(H) mutation, and defects of the TP53 gene. However, disruption of the p53 pathway can occur through mechanisms other than TP53 mutation, and we have recently developed a simple screening test that detects p53 dysfunction due to mutation of the genes encoding either p53 or ATM, a kinase that regulates p53. The present study was conducted to examine the predictive value of this test and to establish the relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation. CLL cells from 71 patients were examined for IgV(H) mutation, CD38 expression, and p53 dysfunction (detected as an impaired p53/p21 response to ionizing radiation). Survival data obtained from 69 patients were analyzed according to each of these parameters. Relative lack of IgV(H) mutation (less than 5%; n = 45), CD38 positivity (antigen expressed on more than 20% of malignant cells; n = 19), and p53 dysfunction (n = 19) were independently confirmed as adverse prognostic factors. Intriguingly, all p53-dysfunctional patients and all but one of the CD38(+) patients had less [corrected] than 5% IgV(H) mutation. Moreover, patients with p53 dysfunction and/or CD38 positivity (n = 31) accounted for the short survival of the less mutated group. These findings indicate that the poor outcome associated with having less than 5% IgV(H) mutation may be due to the overrepresentation of high-risk patients with p53 dysfunction and/or CD38 positivity within this group, and that CD38(-) patients with functionally intact p53 may have a prolonged survival regardless of the extent of IgV(H) mutation.

ADP-ribosyl Cyclase↗