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Class III receptor tyrosine kinases: role in leukaemogenesis

Haematopoiesis is a critically regulated process in which a small population of self-renewing primitive progenitors generate progeny of increasingly differentiated end cells with specific functional activities. This process is controlled by a number of growth factors and cytokines, with some of them exerting their specific functions through binding to high-affinity receptor tyrosine kinases (RTKs). The human genome, as currently sequenced, is thought to contain 90 tyrosine kinase genes, of which 58 are of the receptor type. The latter have been grouped into 20 subfamilies based on kinase domain sequence, a feature that also parallels their overall domain structure (Robinson et al, 2000). Class III RTKs (Ullrich & Schlessinger, 1990) are characterized by five immunoglobulin-like domains in the extracellular ligand-binding region, a single transmembrane domain (TM), a juxtamembrane domain (JM), two intracellular kinase domains (TK1 and TK2) divided by a kinaseinsert domain (KI), and a C-terminal domain (Yarden et al, 1987) (Fig 1). Ligand binding to RTKs promotes receptor dimerization and subsequent activation of intrinsic tyrosine kinase activity that results in transphosphorylation of specific tyrosine residues (Weiss & Schlessinger, 1998). The tyrosine-phosphorylated receptor then serves as a docking site for an array of intracellular signalling molecules, including the GTPase-activating protein (GAP), the p85 subunit of phosphatidyl-inositol 3¢-kinase (PI3K), phospholipase C-c (PLC-c), the protein tyrosine phosphatase SHP1, Grb2 and Src-like non-receptor kinases (Rosnet et al, 1996; Porter & Vaillancourt, 1998). These activated proteins then initiate serine ⁄ threonine phosphorylation cascades resulting in activation of transcription factors that determine a variety of cell responses, including cell maintenance, mitogenesis, migration and differentiation (Claesson-Welsh, 1994). The class III RTKs, which include c-fms (Coussens et al, 1986), c-kit (Yarden et al, 1987), FLT3 (Rosnet et al, 1993a), PDGFRa (Claesson-Welsh et al, 1989) and PDGFRb (Yarden et al, 1986), play an important role in normal haematopoiesis (with the exception of PDGFRa). c-fms, the receptor for the macrophage colony-stimulating factor (M-CSF), is crucial for the growth and differentiation of the monocyte–macrophage–osteoclast lineage (Sherr, 1990). FLT3 and c-kit are both required for the survival, proliferation and differentiation of haematopoietic progenitor cells, while c-kit is also important for the growth of mast cells, melanocytes, primordial germ cells and interstitial cells of Cajal (Drexler, 1996; Lyman & Jacobsen, 1998). The haematopoietic functions of PDGFRb are less well defined, although the receptor and its’ ligand probably play a significant role in megakaryocytopoiesis (Yang et al, 1997). The chromosomal location and genomic structure of the class III RTKs suggests a close evolutionary relationship. The c-kit and PDGFRa genes, for example, are located in tandem on chromosome subregion 4q11–q13 (Gronwald et al, 1990; Giebel et al, 1992), while the PDGFRb gene lies approximately 350 base pairs upstream of the major transcription site of the c-fms gene on chromosome segment 5q31–q33 (Groffen et al, 1983; Roberts et al, 1988). The human FLT3 gene maps to 13q12 (Rosnet et al, 1991) and is closely linked, in a head-to-tail fashion, to FLT1, a class V RTK (characterized by seven immunoglobulin-like domains) (Rosnet et al, 1993b; Imbert et al, 1994). Recently, the FLT3 gene has been shown to comprise 24, rather than the expected 21, exons typical of other class III RTKs, with seven instead of four exons encoding the first three immunoglobulin-like repeats (Abu-Duhier et al, 2001a). In contrast, the genomic loci encoding the intracellular catalytic domains share overall conservation of exon size, number, sequence and exon ⁄ intron boundary positions, suggesting that they have arisen from a common ancestral gene by cis and trans duplication (Andre et al, 1992, 1994; Rosnet et al, 1993b; Abu-Duhier et al, 2001a). The PDGFRa and c-fms genes also contain a large intron (more than 20 kb) that disrupts the 5¢-untranslated region and the signal sequence containing the initiator AUG codon. These large introns may have been inserted prior to the cis duplication of the ancestral gene, because such an insert is not present in the c-kit gene (Kawagishi et al, 1995). In view of the pivotal role of class III RTKs in normal haematopoiesis, many groups have sought evidence for their involvement in leukaemia and related disorders. The aim of this review is to provide a focused update of this work and to emphasize the importance of c-kit, FLT3 and PDGFRb mutations in the pathogenesis of myeloid disorders. Emphasis is given to the considerable insight that such research has provided into the structure–function relationship of class III RTKs and their associated signal transduction pathways. Indeed, a better understanding of their role in leukaemogenesis may offer novel approaches for the development of more selective and less toxic antileukaemic therapy.