Chronic Myelocytic Leukemia - Part I: History, Clinical Presentation, and Molecular Biology

Clinical Laboratory Science, Winter 2005 by Randolph, Tim R

NORMAL PROTEIN PRODUCT OF THEABL GENE (p145)

P145 is the gene product of the normal c-abl protooncogene, and is a nuclear protein with non-receptor, tyrosine kinase activity. The p 145 protein has been shown to migrate between the nucleus and cytoplasm.13,14 This activity has been linked to cellular growth control by being associated with several growth factor receptors like epidermal growth factor (EGF), platelet derived growth factor (PDGF), and colony stimulating factor (CSF). The protein p 145 is found in Drosophila and functions in the regulation of normal cell proliferation. It is also highly conserved in vertebrates and strongly expressed in hematopoietic cells. Based on this information, it is generally accepted that p 145 is involved in signal transduction pathways through the phosphorylation and subsequent activation of nuclear proteins.

Signal transduction pathways are biochemical pathways that, through a series of molecular reactions, transmit a signal through the cytoplasm, to the nucleus. The signal is usually initiated by a ligand/receptor interaction at the cell surface that sets the pathway in motion. Nuclear proteins will be stimulated to bind DNA and facilitate the activation of select genes. The protein products of these genes will serve a specific function in the cell, growth control in the case of CML. The functional domains of p 145 are illustrated in Figure 3a. The myristoylation site near the amino terminus functions to localize the protein to the nucleus. The SH3 domain suppresses tyrosine kinase activity and therefore functions to down regulate cell proliferation. SH2 domain interacts with tyrosine-phosphorylated proteins, essentially holding them in place so the SH1 domain can perform the actual phosphorylation function. In most signal transduction pathways the phosphorylation of target messenger proteins activates the proteins to turn on the pathway. The C-terminal domains are poorly defined but seem to function to bind nuclear proteins, DNA, and actin.

NORMAL PROTEIN PRODUCT OF THE BCR GENE (p160)

The normal function of p 160 protein, transcribed from the BCR gene, is less well understood. It is constitutively expressed in many cell lines and strongly expressed in hematopoietic cells. The important functional domains are illustrated in Figure 3a. The coiled-coil motif is essential for polymerization with other proteins. The dimerization domain (DD) facilitates the formation of protein dimers. The tyrosine residue at position 177 is of particular importance in that it is an essential contact point for the binding of signal traiisduction proteins. The next functional domain to the right is the serine/threonine kinase domain that serves as the catalytic domain for phosphorylation activity. The GEF domain stands for GDP/GTP exchange factor and functions to compete with other GTP binding proteins for GTP, which is used as the phosphate donor for phosphorylation reactions. The RAC GAP domain controls the rate of GTP hydrolysis and is sometimes called RAS-like GTPase. The RAS GAP domain functions by converting active RAS proteins to their inactive form, when bound to GDR So both proteins appear to function in the phosphorylation of other proteins involved in signal transduction pathways that serve to stimulate and regulate cell growth.