Survival mechanisms in B lymphoid malignancies and associated therapies

Abstract

The apoptotic pathway plays critical roles in regulating lymphocyte survival throughout B cell development, maturation and differentiation. The whole process involves clonal expansion. In the normal B lymphocyte population the majority of cells and their progenitors derived from each stage die from induction of apoptosis under specific mechanisms of control. Failure to do so can result in malignant transformation. This project focuses on apoptotic pathways and associated survival mechanisms in neoplasms of lymphoid provenance with an emphasis on B cell malignancies. The role of galectin-3, a molecule implicated in signal transduction and apoptotic pathways, has been investigated in both primary CLL cells and cell lines of human B lineage, using GCS-100, a novel galectin-3 antagonist. The potential interaction between galectin-3 and Bcl-2 and its contribution to cell death have been explored in depth. The role of NADPH oxidase and ROS in mitochondria has also been examined in the context of apoptosis. PK11195, a small proapoptotic molecule, has been studied in relation to mitochondria-mediated apoptosis. The above investigations could contribute to a rationale for potential novel strategies in the treatment of B cell malignancies.