Zoltan Matrai

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.

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 sub-populations 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.

Az IGHV mutációanalízis jelentősége krónikus lymphocytás leukémiában

Absztrakt: Bevezetes: Az elmult evekben megjelent uj celzott terapias szereknek koszonhetően nagy attores tortent a kronikus limfocitas leukemia kezeleseben, kulonosen a magas rizikoju betegcsoport...

Genomikus kópiaszám-eltérések szűrése krónikus limfoid leukémiában multiplex ligációfüggő szondaamplifikációval

Absztrakt: A kronikus limfocitas leukemia klinikailag heterogen megjelenese genetikai diverzitassal parosul. Hazankban fluoreszcens in situ hibridizacio terjedt el a betegekben előfordulo, prognosz...