Heat shock protein expression and apoptosis in myeloid leukaemias

Abstract

The heat shock response was originally described as a phenomenon of inducible gene expression in Drosophila in response to hyperthermia, but has rapidly become recognised as a ubiquitous response by virtually all cell types to a wide variety of environmental stresses. Much of the early work on heat shock protein (hsp) structure and function concentrated on the analysis of heat shock gene expression in Drosophila, but it soon became clear from studies involving higher eukaryotes and prokaryotes that the heat shock response is highly conserved and a high degree of homology in the nucleic acid sequence of related heat shock genes is evident in all species from bacteria to man. Over the past decade, the study of heat shock protein expression has diversified into broad areas of biological research. The importance of heat shock proteins as molecular chaperones which mediate the folding and assembly of polypeptide chains has led to a reexamination and broadening of our understanding of the principles of protein folding and transport. In immunology, heat shock proteins have been shown to act as major antigens involved in the immune response to pathogens, and mechanisms involving heat shock proteins have been implicated in the pathogenesis of a variety of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. At the conception of this research, evidence existed that expression of heat shock proteins was related to the differentiation of cells, including haemopoietic cells, and abnormal expression in some tumour cells had been reported, although not in leukaemic cells. It was against this background that the ideas for this research project were conceived. Based in the Department of Haematology at Warwick Hospital, I had access to samples from leukaemic patients, providing an opportunity to examine heat shock protein expression in malignant cells from these patients. As the project evolved, the significance of lisp expression was addressed by studying the relationship between heat shock protein expression and apoptosis. This mode of cell death has recently been shown to be crucial in carcinogenesis. A tumour is known to develop if the balance between cell division and cell death by apoptosis is disturbed, permitting a potentially malignant clone of cells to escape elimination. In addition, most, if not all, the cytotoxic drugs used to target malignant cells are known to exert their effects via the induction of apoptosis. The expression of genes which influence the susceptibility of cells to chemotherapy-induced apoptosis may therefore have a bearing upon the efficacy of chemotherapeutic regimens. Since heat shock proteins have been shown to protect cells against apoptosis induced by a variety of stresses, their expression in leukaemic cells is particularly worthy of investigation, both in terms of leukaemogenesis and the response of leukaemic cells to chemotherapy. This research project has therefore evolved to question the role of heat shock proteins in the biology and treatment of leukaemia and to establish their role in the control of apoptosis, with particular reference to the stress response of cells exposed to the chemotherapeutic agents used in the treatment and clinical management of these malignancies