CTLA-4 affects expression of key cell cycle regulators of G0/G1 phase in neoplastic lymphocytes from patients with chronic lymphocytic leukaemia.

Lidia Ciszak,Dariusz Wolowiec,Aleksandra Szteblich,Agata Kosmaczewska,Irena Frydecka

doi:10.1007/s10238-015-0360-7

Abstract

Previously, we showed that cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is overexpressed in chronic lymphocytic leukaemia (CLL) and its expression is correlated with the expression of the major regulators of G1 phase progression: cyclins D2 and D3, and cyclin-dependent kinase inhibitory protein 1 (p27KIP1). In the present study, we blocked CTLA-4 on the surface of both CLL cells and normal B lymphocytes to investigate the impact of CTLA-4 on the expression of the mentioned G1 phase regulators. We found that in CLL patients and in healthy individuals, the median proportions of cyclin D2-positive cells as well as cyclin D3+ cells significantly decreased following CTLA-4 blockade. Moreover, CTLA-4 blockade led to an increase in the median frequencies of p27KIP1-positive cells, although this increase was marked only in CLL patients. Our study showed that CTLA-4 affects the expression of the key regulators of G1 phase progression in CLL cells as well as in normal B lymphocytes and may contribute to a better understanding of the role of CTLA-4 in the regulation of G1 phase progression.

Highlights

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in Western Europe and North America
Previously, we showed that cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is overexpressed in chronic lymphocytic leukaemia (CLL) and its expression is correlated with the expression of the major regulators of G1 phase progression: cyclins D2 and D3, and cyclin-dependent kinase inhibitory protein 1 (p27KIP1)
Literature data confirm that CLL cells bear the phenotype of activated B cells based on overexpression of the classical activation markers CD23, CD25, CD69 and CD71, and under-expression of CD22, Fcc IIb, CD79b, and immunoglobulin D, which are down-regulated by cell triggering and activation [34]

Summary

Introduction

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in Western Europe and North America. It has been described as a progressive accumulation of malignant, morphologically mature CD19?CD5? It is becoming increasingly evident that the cells located in the proliferation centres (PCs) of lymph nodes and bone marrow proliferate more than previously anticipated [13], and CLL patients with higher birth rates are much more likely to exhibit active or to develop progressive disease than those with lower birth rates [13]. The proliferating cells in PCs represent the CLL proliferating reservoir that replenishes the downstream accumulation compartment

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