Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease

Abstract

Tyrosine kinase oncogenes are formed as a result of mutations that induce constitutive kinase activity. Many of these tyrosine kinase oncogenes that are derived from genes, such as c-Abl, c-Fes, Flt3, c-Fms, c-Kit and PDGFRβ, that are normally involved in the regulation of hematopoiesis or hematopoietic cell function. Despite differences in structure, normal function, and subcellular location, many of the tyrosine kinase oncogenes signal through the same pathways, and typically enhance proliferation and prolong viability. They represent excellent potential drug targets, and it is likely that additional mutations will be identified in other kinases, their immediate downstream targets, or in proteins regulating their function.

Introduction

Phosphorylation of tyrosine residues is a conserved mechanism throughout evolution to transmit activating signals from the cell surface or specialized cellular structures to cytoplasmic proteins and cell nucleus. A large family of tyrosine kinases has been identified, which largely can be classified as receptor and non-receptor tyrosine kinases (Blume-Jensen and Hunter, 2001). Receptor tyrosine kinases (RTKs) mediate cellular responses to a broad array of extracellular signals involved in the regulation of cell proliferation, migration, differentiation and survival signaling. Ligand binding to the receptor initiates a cascade of events, including receptor homodimerization, activation of intrinsic kinase activity, intermolecular tyrosine trans-phosphorylation, association with signal-transducing proteins and phosphorylation of substrates (Weiss and Schlessinger, 1998). Phosphorylated tyrosine residues within specific sequence contexts serve as high-affinity docking sites for Src homology 2 (SH2) domains-containing adaptor and effector molecules. Adaptors do not contain intrinsic catalytic activity but consist of independent functioning interaction modules like SH2-domain (mediates binding to phosphotyrosine residues), SH3-domain (interacts with polyproline-rich PXXP stretch) or pleckstrin homology (PH) domain (binds to inositol lipids).

The first tyrosine kinase oncogene associated with human hematologic disease, Bcr–Abl, was identified almost twenty years ago, and there is now evidence for involvement of multiple tyrosine kinase oncogenes in acute and chronic leukemias, lymphomas, and myelomas. In each case, the tyrosine kinase activity of the oncogene is constitutively activated by mutations that result in dimerization or clustering, removal of inhibitory domains, or induce the kinase domain to adopt an activated configuration. Activated tyrosine kinase oncogenes generally cause enhanced proliferation and prolonged viability, but do not typically block differentiation. Common signaling pathways are involved in mediating these effects, including activation of phosphotidylinositol 3-kinases (PI3K), the Ras/Raf/MAP kinases, phospholipase C-γ (PLCγ), and Signal transducers and activators of transcription (Stats). On the other hand, tyrosine kinase oncogenes seem to be associated with either lymphoid or myeloid disorders. It is not clear yet if some of the oncogenes have a predilection for transforming one lineage rather than another, or if the lineage association is conferred by the expression pattern of the translocation fusion partner or modified by cooperating oncogenes.

In this review, we will discuss a number of tyrosine kinase oncogenes associated with hematopoietic neoplasia. Both unique and shared features will be emphasized. Their role in normal hematopoiesis as well as other relevant biological functions will be considered, and signaling mechanisms described in more detail.

Abl kinase family

c-Abl/ARG

The mammalian Abl family of non-receptor tyrosine kinases consists of c-Abl and ARG (Abl-related gene), which share 89, 90 and 93% identity in their Src homology region (SH) 3, SH2 and tyrosine kinase domain, respectively. The overall sequence identity in the C-terminal half of the proteins is only 29% with conservation of the proline-rich region and interaction sites for globular (G)- and filamentous (F)-actin (Kruh et al., 1990). In contrast to c-Abl, there is no evidence for DNA-binding activity of ARG, and three NLS sequences present in c-Abl are not conserved in ARG. Consequently, c-Abl shows both cytoplasmic and nuclear localization, whereas ARG has been detected predominantly in the cytoplasm (Wang and Kruh, 1996). The human c-ABL and ARG genes are expressed ubiquitously and each gene contains two alternative 5′ exons, generating two variant protein products denoted as type Ia and Ib. The type Ib variant contains a consensus sequence for N-terminal myristylation. The c-Abl proto-oncogene was originally identified as the cellular counterpart of v-Abl, encoded by the Abelson murine leukemia virus. Subsequently, it was demonstrated that c-Abl is involved in two different chromosomal translocations present in human leukemias, which generate the Bcr-Abl (p185, p210 and p230) and TEL–Abl proteins (Andreasson et al., 1997; Golub et al., 1996; Papadopoulos et al., 1995). More recently, TELARG fusion transcripts have been identified in acute myeloid leukemias (AML) with a t(1;12)(q25;p13) translocation (Cazzaniga et al., 1999; Iijima et al., 2000), arguing that both Abl tyrosine kinase family members have oncogenic potential.

Mice with a true null mutation for c-Abl show with a variable penetrance neonatal lethality, runted and dwarf appearance, lymphopenia with increased susceptibility to bacterial infections and defective craniofacial and eye development (Tybulewicz et al., 1991) (Table 1). Interestingly, mice containing a truncated C-terminus of c-Abl with intact kinase activity display a similar phenotype, arguing that C-terminal interacting proteins are critical for the biological activity of c-Abl (Schwartzberg et al., 1991). Targeted disruption of the arg gene results in largely normal mice, exhibiting some behavioral abnormalities, while embryos deficient for both c-Abl and Arg display defective neurulation, increased apoptosis and hemorrhage, and die around 10.5 days post coitum (Koleske et al., 1998) (Table 1). Studies in c-abl−/−/arg−/− neuroepithelial cells show gross alterations in their actin cytoskeleton. Direct interaction of Abl family kinases with G- and F-actin (Van Etten et al., 1994), as well as cytoskeletal-associated proteins Hef1 (Law et al., 1996), amphiphysin-like protein 1 (ALP1) (Kadlec and Pendergast, 1997), Arg binding protein 2 (ArgBP2) (Wang et al., 1997), paxillin (Lewis and Schwartz, 1998) and c-Crk II (Escalante et al., 2000) may therefore be of great significance to coordinate cytoskeletal functions. Interestingly, recent data show that c-abl−/−/arg−/− fibroblasts display increased motility, and argue that both c-Abl and Arg negatively regulate cell migration by disrupting Crk-p130CAS complex formation (Kain and Klemke, 2001).

Table 1 Overview in vivo phenotypes of tyrosine kinase gene-deficient mice

Several lines of evidence suggest a positive role of c-Abl in cell cycle regulation. In quiescent and G1 cells, nuclear c-Abl is kept in an inactive state by the retinoblastoma protein (pRB), which binds to the ATP-binding cleft within the tyrosine kinase domain of c-Abl thereby inhibiting its kinase activity. Phosphorylation of pRB by cyclin D-Cdk4/6 disrupts the c-Abl/pRB complex at the G1/S transition and results in the activation of Abl tyrosine kinase during S phase (Welch and Wang, 1993). In S phase, c-Abl is able to contribute to the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II, possibly promoting transcription elongation (Baskaran et al., 1993; Duyster et al., 1995). Conversely, c-Abl abrogates pRB-mediated growth arrest in SAOS-2 cells, which are deficient in pRb as well as p53 (Welch and Wang, 1995). Abl interacts directly with transcription factors CREB and E2F-1, thereby stimulating their transcriptional activity (Birchenall-Roberts et al., 1995, 1997). Fibroblasts deficient of c-Abl displayed delayed entry into S-phase upon PDGF stimulation (Plattner et al., 1999), while c-abl−/− B lymphocytes show reduced mitogenic response to interleukin (IL)-7 and LPS (Hardin et al., 1996). Furthermore, c-Abl contributes to enhanced proliferation of p53-deficient cells (Whang et al., 2000).

On the other hand, overexpression of c-Abl results in a G1-arrest that requires its nuclear localizing signals, SH2 domain and tyrosine kinase activity and is dependent on wild-type p53 and Rb (Sawyers et al., 1994; Wen et al., 1996). c-Abl also has been shown to activate programmed cell death independent of pRB and p53 (Theis and Roemer, 1998; Yuan et al., 1997a). These effects relate to the ability of c-Abl to induce a G1-arrest and subsequent apoptosis in response to cellular genotoxic stress. DNA damage due to ionizing radiation (IR) or cytotoxic drugs leads to activation of c-Abl, which is dependent on DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) kinase (Baskaran et al., 1997; Shafman et al., 1997). Subsequently, c-Abl interacts with p53 and enhances p53-mediated transcription and growth suppression (Yuan et al., 1996). In addition c-Abl promotes nuclear accumulation of p53 by preventing ubiquitination and nuclear export of p53 by Mdm2 (Sionov et al., 2001). Furthermore, in response to DNA damage c-Abl phosphorylates Rad51, prohibiting its function in DNA double-strand break repair and genetic recombination (Chen et al., 1999; Yuan et al., 1998), and phosphorylates the p53-related protein p73, where c-Abl stimulates its transcriptional activity and promotes p73 protein stability (Agami et al., 1999; Gong et al., 1999; Yuan et al., 1999). Most likely, p53 and p73 represent distinct effectors activated after genotoxic stress, since targeted gene-inactivation experiments reveal non-overlapping functions for both genes.

Activation of c-Abl upon DNA damage is also reported to contribute to the induction of Jun kinase (JNK/SAPK) and p35 MAPK pathways, which are involved in the induction of apoptosis. Cells deficient in c-Abl fail to activate JNK/SAPK and p38 MAPK after treatment with certain DNA-damaging agents (Kharbanda et al., 1995; Pandey et al., 1996), which correlates with the ability of c-Abl to bind and stimulate the activity of the upstream effectors MEK kinase 1 (MEKK1) and hematopoietic progenitor kinase 1 (HPK1) in response to genotoxic stress (Ito et al., 2001; Kharbanda et al., 2000). Additionally, it has been demonstrated that the p85 subunit of PI3K (p85-PI3K) interacts with c-Abl, where tyrosine phosphorylation of p85-PI3K in response to DNA damage negatively regulates PI 3-kinase activity (Yuan et al., 1997b). Whereas DNA damage activates directly the nuclear form of c-Abl, oxidative stress induces activation of cytoplasmic c-Abl, which results in the phosphorylation of protein kinase C δ (PKCδ) (Sun et al., 2000b). Moreover, c-Abl kinase activity is required for oxidative stress-induced mitochondrial cytochrome c release and apoptosis (Sun et al., 2000a). Thus, multiple signaling pathways may contribute to the induction of apoptosis after activation of c-Abl under cellular stress-conditions.

Bcr-Abl

Chronic myelogenous leukemia (CML) is a clonal disorder of multipotential hematopoietic stem cells (HSCs), and virtually all cases contain the t(9;22) (q34;q11) translocation characteristic of the Philadelphia (Ph) chromosome, which is associated with the presence of p210Bcr–Abl. The p185Bcr–Abl is characteristic for Ph+ acute lymphocytic leukemia (ALL), while p230Bcr–Abl has been detected in chronic neutrophilic leukemia. All Bcr–Abl variants contain elevated tyrosine kinase activity compared to c-Abl, but among the three forms, p185Bcr–Abl shows the strongest activity. Whereas each Bcr–Abl protein harbors the coiled-coil (CC) oligomerization domain (amino acids 1–63) and the serine/threonine kinase domain (amino acids 64–414) in the Bcr region, the Dbl/CDC24 guanine nucleotide exchange factor (GEF) homology (Dbl) domain and pleckstrin homology (PH) domain (amino acids 734–866) are absent in p185Bcr–Abl. The CC oligomerization domain is critical for transformation and induces tetramerization of Bcr–Abl that is required for the constitutive activation of the tyrosine kinase of Bcr–Abl (McWhirter et al., 1993). Additional domains within Bcr that are relevant for efficient oncogenic transformation by p210Bcr–Abl include two SH2-binding regions (amino acids 176–242 and amino acids 298–413) (Pendergast et al., 1991), and Dbl domain (Kin et al., 2001).

Transforming capacity of Bcr–Abl is weak in Rat1 fibroblasts, but is evident in hematopoietic cells and requires the presence of a functional protein kinase domain. Activation of Ras, Raf, PI3K, and JNK/SAPK signaling pathways (Dickens et al., 1997; Sawyers et al., 1995, Skorski et al., 1995a,b, 1997), as well as transcriptional activation of NF-κB, c-Jun and c-Myc are required for Bcr–Abl-induced transformation (Raitano et al., 1995; Reuther et al., 1998; Sawyers et al., 1992). Cooperation between multiple signaling pathways, including Ras and PI3K, is required for the full oncogenic activities of Bcr–Abl (Sonoyama et al., 2002). Additionally, Stat5 is constitutively activated by tyrosine phosphorylation in Bcr–Abl-transformed cells (Carlesso et al., 1996; Ilaria and Van Etten, 1996), which is required for their growth and viability (Gesbert and Griffin, 2000; Sillaber et al., 2000). However, myeloid cells deficient in Stat5a/b display unaltered transformation efficiency by p210Bcr–Abl (Sexl et al., 2000).

Bcr–Abl inhibits apoptosis in cells exposed to DNA damage, cytokine deprivation and Fas activation, which involves several mechanisms blocking mitochondrial release of cytochrome c and procaspase-3 activation (Amarante-Mendes et al., 1998b; Dubrez et al., 1998). These include Bad phosphorylation (Neshat et al., 2000), and induction of Bcl2 and Bcl-xL levels (Amarante-Mendes et al., 1998a; Sanchez-Garcia and Grutz, 1995). Activation of Stat5 and inhibition of caspase-3 cleavage by Bcr–Abl result in overexpression of Rad51 and its paralogs, leading to increased drug resistance (Slupianek et al., 2001b). Furthermore, Bcr–Abl-mediated down-regulation of p27Kip1 levels may contribute to enhanced survival signaling in hematopoietic cells (Gesbert et al., 2000; Jonuleit et al., 2000; Parada et al., 2001).

Besides its established role in preventing programmed cell death, the effects of Bcr–Abl on hematopoietic cell differentiation are less well defined. Bcr–Abl increases the myeloid cell compartment after retroviral transduction of murine bone marrow, but does not alter the fundamental potential of HSC to differentiate along lymphoid, myeloid or erythroid lineages (Li et al., 1999). This is consistent with the clinical phenotype of stable phase human CML. However, Bcr–Abl can prevent G-CSF-mediated differentiation of the myeloid precursor cell line 32D, by inducing the expression of the RNA-binding protein hnRNP-E2, thereby suppressing C/EBPα translation and consequently transcriptional activation of granulocyte colony-stimulating factor receptor (G-CSF-R) (Perrotti et al., 2002).

Bcr–Abl is constitutively phosphorylated on many tyrosine residues, of which only a few have been mapped, including Tyr-177 within the Bcr region and Tyr-1294 in the Abl kinase domain. Tyr-177 serves as a docking site for adaptor protein Grb2, and this interaction is critical for Bcr–Abl-induced transformation (Pendergast et al., 1993). Grb2 recruits the Ras GTP/GDP exchange factor mSOS (Egan et al., 1993) and Bcr–Abl-mediated phosphorylation of Grb2 inhibits binding to mSOS (Li et al., 2001). Grb2 also associates with tyrosine phosphatase Shp2 and p85 regulatory subunit of PI3K (p85-PI3K) (Tauchi et al., 1997). Shp2 on its turn can form a complex with dual adaptor/inositol 5-phosphatase SHIP1 (Sattler et al., 1997a). Adaptor molecules Shc and Grap may act as alternative pathways from Bcr–Abl to Ras (Feng et al., 1996; Puil et al., 1994; Tauchi et al., 1994). On the other hand, Ras GTPase activating protein (RasGAP) interacts with the highly phosphorylated protein p62Dok1 (Carpino et al., 1997; Yamanashi and Baltimore, 1997), or its homolog p56Dok2 (Di Cristofano et al., 1998), and tyrosine phosphorylation of p62Dok1 by Bcr–Abl inhibits RasGAP activity.

Apart from Grb2, also Cbl and Crkl serve as important intermediate signaling proteins for linking Bcr–Abl to the major effector pathways (Figure 1). Cbl, the cellular homolog of the v-Cbl oncoprotein, binds to the Abl–SH2 domain and recruits p85-PI3K (Sattler et al., 1996). Cbl forms a complex with Grb2 (Jain et al., 1997) and associates with focal adhesion proteins paxillin and talin (Salgia et al., 1996b). Crkl was identified as one of the major tyrosine phosphorylated proteins in CML neutrophils and Bcr–Abl-expressing cell lines (Oda et al., 1994). Abl as well as the guanine nucleotide exchange factors mSOS and C3G interact with Crkl-SH3 domains (Feller et al., 1995). On the other hand, the SH2 domain of Crkl serves as a docking site for Cbl (de Jong et al., 1995), SHIP1 (Sattler et al., 2001), activator of the JNK/SAPK pathway GCKR (Germinal Center Kinase Related) (Shi et al., 2000), cytoskeletal-associated proteins p130CAS (Salgia et al., 1996a), Hef1/Cas-L (de Jong et al., 1997), and paxillin (Salgia et al., 1995). The abl interactor (Abi) proteins (Dai and Pendergast, 1995; Shi et al., 1995), which have been implicated in Rac-dependent cytoskeletal reorganization, provide alternative ways for Bcr–Abl to control cytoskeletal function. DokL (Cong et al., 1999), Grb10 (Bai et al., 1998b), Gads (Liu and McGlade, 1998) and Nckβ (Coutinho et al., 2000) are additional adaptor proteins that associate with Bcr–Abl, while PLCγl (Gotoh et al., 1994), Vav (Matsuguchi et al., 1995), c-Fes (Ernst et al., 1994), Src kinases Hck and Lyn (Danhauser-Riedl et al., 1996) and Rin1 (Afar et al., 1997) are tyrosine phosphorylated in cells expressing Bcr–Abl.

Figure 1
figure3

Schematic diagram showing the various structural motifs within p210Bcr-Abl and interacting signaling molecules. Amino acids 1–63 encode for the coiled-coil (CC) oligomerization domain, which is followed by the serine/threonine kinase domain (Ser/Thr KD), the Dbl/CD24 guanine nucleotide exchange factor (GEF) homology domain (Dbl) and pleckstrin homology (PH) domain in the Bcr region of the fusion protein. The Abl sequence harbors Src homology 3 (SH3) and SH2 domains, the catalytic tyrosine kinase domain (Tyr KD), a stretch rich in proline sequences (P-P-P), DNA binding domain and interaction site for globular (G-) and filamentous (F-) actin. Adaptor protein Grb2 interacts with Bcr phosphotyrosine 177 (Y177) via its SH2 domain, whereas the SH2 domain of Abl associates with phosphotyrosine residues in Dok1 and Cbl. Crkl binds via its SH3 domain to the proline rich stretch in Abl. Arrows indicate interactions between distinct signaling proteins

It has been a difficult challenge to recapitulate the p210Bcr–Abl-induced chronic myeloid disease in a mouse model (Wong and Witte, 2001). Transgene-driven expression of Bcr–Abl has predominantly resulted in lymphoid malignancies (Honda et al., 1995; Voncken et al., 1995), whereas in Tec-p210Bcr–Abl transgenic mice an overt myeloproliferative disease (MPD) occurs only after a long latency (Honda et al., 1998). A murine bone marrow retroviral transduction/transplantation (BMT)-based approach has proven to be more successful (Pear et al., 1998; Zhang and Ren, 1998). Whereas p185, p210 and p230 are associated with distinct clinical entities in humans, all three Bcr–Abl variants are equally potent in inducing a CML-like disease in transplanted mice (Li et al., 1999). Down regulation of transcription factor Interferon Consensus Sequence Binding Protein (ICSBP) is essential for induction of MPD by Bcr–Abl (Hao and Ren, 2000). In the absence of the proline-rich stretch, the SH2 or SH3 domain, Bcr–Abl is not compromised in its ability to elicit a MPD, only the latency of the disease is extended (Gross et al., 1999; Roumiantsev et al., 2001; Zhang et al., 2001b). In contrast, deletion of both the SH3-domain and proline-rich stretch, or the N-terminal CC domain, or mutation of the Grb2 binding site Tyr-177 severely impair the development of a CML-like disease (Dai et al., 2001; Zhang et al., 2001a), suggesting that Bcr as well as Abl sequences play an important role in the onset of chronic myeloid leukemia.

ALK

Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase, highly related to the leukocyte tyrosine kinase (LTK), whose expression is normally restricted to specific regions of the central and peripheral nervous system (Iwahara et al., 1997; Morris et al., 1997). Initially, ALK was found as an oncogene tyrosine kinase fused to nucleolar protein B23/nucleophosmin (NPM) (Morris et al., 1994; Shiota et al., 1994), a ubiquitously expressed RNA-binding nucleolar phosphoprotein capable of shuttling newly synthesized proteins between nucleolus and cytoplasm (Borer et al., 1989). The chimeric gene NPMALK is produced by the chromosomal translocation t(2;5)(p23;q35) (Bitter et al., 1990; Mason et al., 1990; Morris et al., 1994; Wellmann et al., 1995), and is present in approximately 30 to 50% of anaplastic large-cell lymphomas (ALCL), which forms a subgroup of non-Hodgkin lymphoma that often express the membrane antigen CD30 and mainly consists of T/null cells (Stein et al., 2000). Fusion of the N-terminal domain of NPM (amino acids 1–117) to the cytoplasmic region of the ALK receptor (amino acids 1059–1620) generates an 80 kD NPM–ALK fusion protein which forms homodimers, resulting in the constitutive activation of the catalytic ALK tyrosine kinase domain (Bischof et al., 1997; Fujimoto et al., 1996).

NPM–ALK is capable of transforming rodent fibroblasts (Bai et al., 1998a; Bischof et al., 1997; Fujimoto et al., 1996), primary mouse bone marrow cells (Bai et al., 2000) and induces B cell lymphomas in mice after retroviral gene transfer (Kuefer et al., 1997). Immunostaining for ALK in ALCL tumors and transfected cell lines reveals both nuclear and cytoplasmic localization of NPM–ALK (Bischof et al., 1997; Falini et al., 1999; Mason et al., 1998; Wlodarska et al., 1998). Although the NPM region is essential for oncogenic transformation by NPM–ALK, nuclear localization, which occurs through heterodimerization with NPM and its associated shuttling activity, is not required for tumorigenesis (Bischof et al., 1997; Mason et al., 1998). NPM–ALK is able to associate with the adaptor proteins IRS-1 (Tyr-156), Shc (Tyr-567), Grb2, Grb7, Grb10, Gab2, and Crkl (Bai et al., 1998a, 2000; Fujimoto et al., 1996). Interaction of NPM–ALK with PLCγl at Tyr-664 is critical for IL-3-independent proliferation of Ba/F3 lymphocytes and transformation of Rat1 cells (Bai et al., 1998a), whereas activation of PI3K, Akt and Stat5 are required for growth factor-independent survival and transformation (Bai et al., 2000; Nieborowska-Skorska et al., 2001; Slupianek et al., 2001a). Furthermore, NPM–ALK expressing T cell lines display multilevel Stat3 activation (Zhang et al., 2002), and PI3K- and PLCγ-independent drug-resistance (Greenland et al., 2001).

Several reports showed that 15 to 28% of ALK+ lymphomas were negative for the t(2;5) translocation, suggesting the existence of variant X-ALK fusion proteins (Benharroch et al., 1998; Falini et al., 1998, 1999; Pulford et al., 1999). Indeed, various studies have identified alternative fusion partners of the ALK cytoplasmic domain in ALCL (Figure 2). These include the nonmuscle tropomyosins TPM3 and TPM4 at t(1;2)(q21;p23) and t(2;19)(p23;p13.1) respectively (Lamant et al., 1999; Meech et al., 2001; Siebert et al., 1999), two different variants of TFG (tropomyosin receptor kinase-fused gene) at t(2;3)(p23;q21) (Hernandez et al., 1999), the clathrin heavy chain gene CLTC (and not CLTCL) at t(2;17)(p23;q23) (Morris et al., 2001; Touriol et al., 2000), the ERM protein moesin (MSN) at t(2;X)(p23;q11-12) (Tort et al., 2001), and the bifunctional enzyme ATIC (5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleotide transformylase/inosine monophosphate cyclohydrolase) at inversion (2)(p23;q35) (Colleoni et al., 2000; Ma et al., 2000; Trinei et al., 2000). In contrast to NPM–ALK, all variant fusion proteins are absent from the nucleus and are localized to cytoplasm or plasma membrane, supporting previous findings that the oncogenic potential of ALK is not dependent on its nuclear localization. However, similar to NPM, all other variant fusion proteins contain specific multimerization regions, and each of them is capable of eliciting ALK tyrosine kinase activation.

Figure 2
figure2

Schematic representation of the various anaplastic lymphoma kinase (ALK) fusion proteins and their characteristic features in Alk+ anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMT). ALCL form a subgroup of non-Hodgkin lymphomas (NHL) expressing the cell surface marker CD30, whereas IMTs arise usually in soft tissues and are composed of myofibroblastic spindle cells admixed with inflammatory cells (lymphocytes, eosinophiles, and plasma cells) and collagen fibers. The chromosomal aberration, subcellular localization and the observed or predicted molecular weight of each fusion protein is indicated. Every ALK translocation occurs to the right of the transmembrane (TM) region and preserves the intracellular tyrosine kinase domain. Note that the clathrin heavy chain gene CLTC, and not CLTCL, should be the correctly identified partner of ALK in ALCL. TFGALK chimeric transcripts may consist of two different TFG variants, generating two distinct fusion proteins. The asterisk indicates that the reported translocation involving RanBP2 has not yet been cytogenetically confirmed

Besides its prominent role in CD30+ ALCL, there is considerable amount of data to suggest that constitutive activation of the ALK kinase is also involved in the pathogenesis of an unrelated disease, called inflammatory myofibroblastic tumors (IMT) (Coffin et al., 2001; Griffin et al., 1999). IMTs consist of spindle shaped myofibroblasts with a pseudosarcomatous inflammatory appearance and arise mostly in the abdomen of children and adolescents (Coffin et al., 1998). Immunohistochemistry shows that 60% of IMTs are positive for ALK expression (Cook et al., 2001). Although it has been suggested that IMTs are of nonneoplastic origin, the identification of clonal chromsomal aberrations involving TPM3ALK, TPM4ALK, CLTCALK and RanBP2ALK gene fusion transcripts in IMT argue for a neoplastic process (Bridge et al., 2001; Lawrence et al., 2000; Morris et al., 2001). ALK may therefore not be a lineage specific oncogene tyrosine kinase, but is able to transform different mesenchymal cell types.

c-Fes/Fps

The c-Fes/Fps proto-oncogene is the mammalian equivalent of the v-fes transforming oncogene associated with the Gardner-Arnstein and Snyder-Theilen strains of feline sarcoma virus and the v-fps oncogenes of Fujinami and PRC-type chicken sarcoma viruses (Groffen et al., 1983). Like c-Abl, c-Fes encodes for a non-receptor tyrosine kinase and contains an N-terminal domain with two predicted coiled-coil (CC) regions involved in oligomerization (residues 1 to 450), a central SH2 domain and a carboxy-terminal tyrosine kinase domain (Roebroek et al., 1985). However, Fes lacks a negative regulatory tyrosine phosphorylation site at the carboxy-terminal end, it has no SH3 domain and is not modified by N-terminal myristylation. All three structural domains of p95c-Fes have the potential to regulate the rather constrained Fes kinase activity in vivo. Deletion of the SH2 domain inhibits Fes autophosphorylation on Tyr-713 and Tyr-811, providing evidence for intermolecular trans-phosphorylation, and mutagenesis of the Tyr-713 autophosporylation site within the kinase domain greatly diminishes kinase activity (Hjermstad et al., 1993; Rogers et al., 1996). Finally, mutation or deletion of the first CC domain activates Fes tyrosine activity, which is significantly abrogated by a point mutation in the second CC domain (Cheng et al., 1999, 2001).

In developing and adult tissues, c-Fes mRNA transcripts are mainly evident in hematopoietic progenitor cells and mature granulocytes and monocytes, but can also be detected in vascular endothelial cells, chondrocytes, Purkinje cells, neuronal cells in the molecular layer of the cerebellum and some epithelial cell types (Haigh et al., 1996). Fes tyrosine kinase has been found to localize in cytoplasmic as well as in (peri-)nuclear and plasma membrane fractions (Feldman et al., 1983; Yates et al., 1995), although more recent data demonstrate p93c-Fes protein localization within the Golgi network and cytoplasmic vesicles, arguing for a role of Fes in vesicular trafficking (Zirngibl et al., 2001). Release of Fes transforming activity occurs through the cloning of an additional myristylation signal sequence at the N-terminus, which targets Fes to membranes (Greer et al., 1994), or Src-SH2 domain substitution with concomitant localization at focal adhesions (Rogers et al., 2000).

Fes seems to be activated by several distinct cytokine receptor subunits that lack intrinsic tyrosine kinase activity themselves. The gp130 signal-transducing subunit forms a part of the IL-6-related cytokine subfamily receptors, and is associated with Fes in the absence of receptor stimulation, while Fes becomes tyrosine phosphorylated after IL-6 stimulation (Matsuda et al., 1995). Fes interacts also with the IL-4Rα subunit and becomes tyrosine phosphorylated by JAK1 upon ligand binding (Izuhara et al., 1994; Jiang et al., 2001). The involvement of Fes in mediating signals downstream of the common β (βc) subunit, which is part of the IL-3/IL-5/GM-CSF receptor complex, and the erythropoietin (EPO) receptor are however more controversial. It has been reported that Fes associates with βc in vitro (Rao and Mufson, 1995), and becomes phosphorylated and activated in response to IL-3 and GM-CSF stimulation (Brizzi et al., 1996a; Hanazono et al., 1993a; Park et al., 1998), but this could not be confirmed in other studies (Anderson and Jorgensen, 1995; Linnekin et al., 1995; Quelle et al., 1994). Similarly, in TF-1 cells EPO induces Fes tyrosine phosphorylation and activation (Hanazono et al., 1993b), but this has been challenged by others (Witthuhn et al., 1993).

Identified substrates for the cellular Fes kinase include RasGAP (Hjermstad et al., 1993), Stat3 (Nelson et al., 1998), Cas (Jucker et al., 1997), IRS-2 (Jiang et al., 2001), and Bcr (Maru et al., 1995). Tyrosine phosphorylation of Bcr on Tyr-177 and Tyr-246 by Fes suppresses Bcr serine/threonone kinase activity toward 14-3-3 protein BAP-1 (Li and Smithgall, 1996), but induces association with Grb2/mSOS, the Ras guanine nucleotide exchange factor complex (Maru et al., 1995). Signaling downstream of the IL-4Rα involves Fes-mediated PI3K recruitment and activation of p70S6K but not Akt kinase (Jiang et al., 2001). Ras activity as well as activation of the Rho family of small G proteins Rac and Cdc42 are required for fibroblast transformation of myristylated c-Fes (Li and Smithgall, 1998).

Human myeloid leukemia cell lines, such as HL-60, KG-1, TF-1, THP-1 and U937 that have retained the capacity to undergo differentiation all express c-Fes mRNA levels. In addition, Fes protein levels can be detected in some human and mouse B and T cell lines (Izuhara et al., 1994; MacDonald et al., 1985). Expression of the p93c-Fes protein is especially high in acute and chronic myeloid leukemias (Smithgall et al., 1991), although this may merely reflect the myeloid component of these malignancies. An aberrant truncated c-Fes transcript is expressed in various lymphoma and lymphoid leukemia cell lines, but there is no direct evidence that the encoded 17 kD protein may result in activation of full length Fes (Jucker et al., 1992). Enforced expression of v-fps renders FDC-P1 cells IL-3 independent (Meckling-Gill et al., 1992) and induces T cell lymphomas, (neuro-)fibrosarcomas, hemangiomas and angiosarcomas in transgenic mice (Yee et al., 1989), whereas mice transgenic for myristylated c-Fes develop multifocal hemangiomas, but display no susceptibility for the development of hematopoietic tumors (Greer et al., 1994).

On the contrary, several reports show that c-fes expression correlates with induction of myeloid differentiation (Smithgall et al., 1988; Yu and Glazer, 1987). In fact, c-Fes overexpression restores the capability of K562 leukemic cells to undergo myeloid differentiation (Yu et al., 1989). Inhibition of Fes protein levels by antisense oligodeoxynucleotides in HL60 prevents granulocytic and macrophage differentiation (Ferrari et al., 1994; Manfredini et al., 1993, 1997). However, studies in c-fes−/− mice show that Fes is dispensable for normal development of the myeloid lineage. The only functional defect in Fes-deficient mice relates to the decreased adhesion capacity of c-fes−/− macrophages, which may explain the compromised innate immunity observed in these animals (Hackenmiller et al., 2000) (Table 1). While reduced numbers of B lymphocytes are observed at all stages of B cell development, the myeloid lineage is overrepresented in bone marrow and peripheral hematopoietic tissues. This relates to enhanced Stat3 activation after IL-6 stimulation, and increased Stat3 and Stat5 activation upon GM–CSF stimulation in c-fes−/− macrophages. No differences are observed with IL-3 and IL-10, and c-fes−/− neutrophils display normal patterns of activation. These data argue that endogenous Fes acts primarily in the monocytic lineage as a negative regulator of Stat3 and Stat5 activation, probably by direct sequestering of Stats and competing with the more potent activator Jak3 for Stat phosphorylation.

Flt3

The murine Flt3/Flk-2 receptor was cloned by low stringency hybridization with a c-fms DNA fragment as a probe (fms-like tyrosine kinase 3) (Rosnet et al., 1991), and by degenerate PCR on a fetal liver cDNA library based on the conserved kinase domain of tyrosine kinase receptors (fetal liver kinase 2) (Matthews et al., 1991). The human homologue, alternatively termed stem cell tyrosine kinase-1 (STK-1), encodes a protein of 993 amino acids with 85% identity and 92% similarity with the corresponding mouse Flt3 protein (Rosnet et al., 1993; Small et al., 1994). The Flt3 receptor has the same general structure as four other tyrosine kinase receptors that comprise the type III receptor tyrosine kinases (RTK) subfamily: c-Fms, the receptor for colony-stimulating factor-1 (CSF-1), c-Kit, and both of the receptors for platelet-derived growth factor (PDGFRα and PDGFRβ). Each of these receptor molecules has five immunoglobulin-like (Ig) domains in the extracellular region and a split catalytic domain in the intracellular part of the receptor.

The ligand for the Flt3 receptor (FL) encodes a type 1 transmembrane protein, but soluble and membrane-bound isoforms can be generated as a result of alternative splicing of mRNAs (Hannum et al., 1994; Lyman et al., 1993). The natural occurring soluble FL protein exists of a 65 kD nondisulfide-linked homodimeric glycoprotein comprised of 30 kD subunits, each containing up to 12 kD of N- and O-linked sugars (McClanahan et al., 1996). FL is structurally similar to Kit Ligand (KL) and M-CSF, and the crystal structure of FL shows the presence of a four-helix bundle fold with the two monomers forming an antiparallel dimer (Savvides et al., 2000). FL mRNA transcripts are present in a wide variety of human and mouse tissues, including spleen, thymus, heart, lung, liver and kidney. In contrast, Flt3 receptor is preferentially expressed in primitive CD34+ hematopoietic stem cells, pro-B cells and immature CD4CD8 thymocytes in addition to gonads, placenta and brain. FL mRNAs are found in most hematopoietic cell lines, whereas Flt3 is primarily expressed in pre-B, monocytic and myeloid cell lines (Brasel et al., 1995; Meierhoff et al., 1995). In primary tumors, increased expression of Flt3 is detected on most leukemic samples of AML and B-ALL, but generally only at low levels on T-ALL (Birg et al., 1992; Carow et al., 1996). Interestingly, Flt3 is the most differentially expressed gene that distinguishes a subset of human acute leukemias involving the mixed-lineage leukemia gene (MLL) (high expression) from conventional B-precursor ALL and AML (Armstrong et al., 2002). FL stimulates proliferation and colony formation of the vast majority of adult and pediatric AML-leukemic cells and promotes their survival, although to a variable extent (Lisovsky et al., 1996; McKenna et al., 1996; Piacibello et al., 2000).

As predicted from the Flt3 expression pattern, FL potently enhances the colony-stimulating activity on hematopoietic progenitor cells in synergy with G-CSF, GM–CSF, M-CSF, IL-3, IL-6, IL-11, IL-12 or KL. FL can also support proliferation of murine B cell progenitor cells committed to the erythrocyte, megakaryocyte, eosinophil, or mast cell lineages (Hirayama et al., 1995; Hudak et al., 1995; Jacobsen et al., 1995). No restrictions in species specificity has been observed for the effects of FL, as murine and human FL are active on cells from both species. In vivo administration of FL alone increases granulocytic-monocytic (GM) and multipotent granulocytic-erythroid-monocytic-megakaryocytic (GEMM) colonies fourfold and sevenfold, respectively (Brasel et al., 1996). FL is also able to promote the survival of late myeloid progenitors (Nicholls et al., 1999). FL enhances the production of dendritic cells (DC) from CD34 BM progenitor cells in combination with GM–CSF, TNF and IL-4. In vivo treatment of mice with FL results in a dramatic increase of DC in all primary and secondary lymphoid tissues (Maraskovsky et al., 1996), and in humans it induces both CD11c+ and CD11c subsets (Maraskovsky et al., 2000; Pulendran et al., 2000). Since DC are the most efficient antigen presenting cells (APC) for T cells, FL administration has been shown to inhibit tumor growth and promote tumor regression and immunization in experimental cancer models (Chen et al., 1997; Lynch et al., 1997).

The phosphorylated cytoplasmic domain of murine Flt3 transduces activation signals through direct interaction with Grb2 and the p85 subunit of PI3K, and phosphorylation of SHIP, Shc, Vav, RasGAP and PLCγ (Dosil et al., 1993; Marchetto et al., 1999; Rottapel et al., 1994). Although no specific Tyr residues have been mapped which mediate the interaction with specific signal-transducing molecules, FL stimulation on human Flt3 receptor results in direct association with Grb2 and Socs1, phosphorylation of Cbl, CblB, Shc, SHIP, Shp2, Gab1, Gab2, Stat5a and activation of the MAP kinase pathway (Lavagna-Sevenier et al., 1998a,b; Zhang and Broxmeyer, 2000; Zhang et al., 2000) (Figure 3). In contrast to murine Flt3, human Flt3 has no potential SH2-domain binding site for p85-PI3K in the carboxyl terminus, nor does p85 seem to be phosphorylated upon FL binding (Zhang and Broxmeyer, 1999). Instead, p85-PI3K has been found associated with tyrosine phosphorylated Shp2, SHIP, Gab1, Cbl and CblB. The significance of Stat5a in Flt3 signaling is illustrated by the fact that only Stat5a−/−, and not Stat5b−/−, bone marrow progenitor cells are unresponsive to FL-mediated proliferative effects (Zhang et al., 2000).

Figure 3
figure1

Hypothetical interactions of signaling molecules with human type III receptor tyrosine kinases (RTK). The family of type III RTK consists of Flt3, c-Fms/CSF-1R, c-Kit and PDGFR, which all are implicated in hematological malignancies. Type III RTK are characterized by five immunoglobulin-like domains in the extracellular (EC) region of the receptor, followed by a transmembrane (TM) and juxtamembrane (JM) domain, a split kinase domain (KD) containing a kinase insert (KI) region, and a C-terminal (CT) tail. Characterized autophosphorylation sites are indicated together with their potential interacting adaptor and effector molecules. Dashed arrows suggest substrate phosphorylation through unidentified phosphotyrosine interaction sites and straight arrows implicate indirect mechanism of phosphorylation. Oncogenic point mutations as well as internal tandem duplications (ITD) and juxtamembrane deletions (JMD) are denoted in black boxes (see text)

Detailed analysis in flt3−/− mice has indicated that mainly primitive B lymphoid progenitor cells are affected in the absence of Flt3 expression (Mackarehtschian et al., 1995) (Table 1). However, normal numbers of functional B cells are present in the periphery, and total composition and cell numbers of hematopoietic organs and peripheral blood are indistinguishable between flt3−/− and wild-type mice. Although the Flt3 receptor is expressed on murine and human cell populations enriched for hematopoietic stem and progenitor cells, the population of multipotential and myeloid colony-forming progenitors is not affected in flt3−/− mice. Only competitive repopulation experiments reveal a significant defect of Flt3-deficient stem cells, where reconstitution of the hematopoietic system is less efficient in comparison to wild-type stem cells, especially of the lymphoid lineage. In contrast, flt3L−/− mice display an overt reduction in leukocyte counts of bone marrow, spleen, lymph nodes and peripheral blood (McKenna et al., 2000). Absolute numbers of CFU-GM are slightly reduced, whereas B-cell precursors show a significant reduction, similar to flt3 receptor-deficient mice. In addition, flt3L−/− mice have decreased numbers of myeloid-related (CD8αCD11chi) and lymphoid-related (CD8α+CD11chi) DC and are deficient in NK cells. At present it is unclear whether these distinct phenotypes reflect true differences between flt3−/− and flt3L−/− mice or relates to mice strain variations.

One important indication implicating Flt3-mediated signaling in the pathogenesis of myeloid leukemia has been the identification of an internal tandem duplication (ITD) in the juxtamembrane (JM) domain of FLT3 in AML (Nakao et al., 1996). Subsequent studies have shown that Flt3 tandem duplications are present in 17–27% of de novo adult AML, 14–17% of childhood AML cases, in 3–5% of MDS, 20% of acute promyelocytic leukemia and 3% of pediatric ALL, expressing myeloid antigens (Kiyoi et al., 1997; Meshinchi et al., 2001; Rombouts et al., 2000; Xu et al., 1999). The presence of ITD in Flt3 correlates with a poor outcome in adult and pediatric AML. Disease-free and overall survival is even more inferior in Flt3-ITD cases lacking the wild type Flt3 allele (Whitman et al., 2001). The length of the ID is variable, but the duplicated sequence is selected for in-frame fusions, and mostly involves the Tyr-rich stretch 587-NEYFYVDFREYEYD-560 located in exon 11. The Flt3-ITD receptor activates Stat5 and the MAP kinase pathway and promotes increased phosphorylation of Akt. Interestingly, in a murine BMT assay, Flt3-ITD, but not wild-type Flt3, even with high expression levels, induces a myeloproliferative phenotype (Kelly et al., 2002). Remarkably, elongation of the JM portion rather than introduction of new tyrosine residues generates ligand-independent dimerized versions of Flt3. However, some tandem duplications in Flt3 show no constitutive autophosphorylation of Flt3 (Fenski et al., 2000). Recently, several kinds of missense mutations at Asp-835 located in the activation loop of the second tyrosine kinase domain of Flt3 have been found in 7% of AML cases and 3% of MDS and ALL cases (Abu-Duhier et al., 2001; Yamamoto et al., 2001). All D835-mutant Flt3 variants induce constitutive tyrosine phosphorylation and confer IL-3-independence in 32D cells. D835 mutations occur independently of Flt3/ITD (Yamamoto et al., 2001), arguing that each variant may contribute to the pathogenesis of acute leukemia.

c-Fms/CSF-1R

The c-fms proto-oncogene encodes for the receptor of colony-stimulating factor-1 (CSF-1), also called macrophage colony-stimulating factor (M-CSF), which is a lineage-specific cytokine stimulating proliferation and differentiation of monocyte progenitors and supporting the survival of mature macrophages (Stanley et al., 1983). The CSF-1R is a transmembrane glycoprotein of 150 kD and belongs to the class III family of intrinsic tyrosine kinase growth factor receptors. The human c-FMS gene is located on chromosome 5q33.3 and is expressed in cells of the monocyte/macrophage lineage, cμ+ pre-B cells, placental trophoblasts, CNS neurons and microglial cells (Arceci et al., 1989; Brosnan et al., 1993; Lu and Osmond, 2001). The importance of CSF-1 in the regulation of the mononuclear phagocyte lineage has been demonstrated by studies with the CSF-1 null mutant osteopetrotic (op/op) mouse (Wiktor-Jedrzejczak et al., 1990). The op/op mouse has impaired bone remodeling due to the absence of osteoclasts, resulting in retarded skeletal growth and excessive accumulation of bone in the first 2 months of age, after which the defects gradually disappear. Other populations of phagocytes are also depleted, including macrophages normally residing in liver, kidney, spleen and gut, whereas lymph node macrophages are relatively intact. CSF-1 appears to act by providing survival signals to mononuclear phagocytic cells, since enforced expression of a bcl-2 transgene in monocytes of mice rescues macrophages and partially reverses osteopetrosis (Lagasse and Weissman, 1997). In addition, op/op mice display primary CNS neuronal deficits, impaired fertility and increased apoptosis of precursor B cells (Lu and Osmond, 2001; Michaelson et al., 1996; Pollard et al., 1991). CSF-1R-deficient mice show a more pronounced but similar osteopetrotic, reproductive, tissue macrophage and hematopoietic phenotypes as op/op mice, including increased splenic erythroid burst-forming units (BFU-E) and high-proliferative potential colony-forming cells (HPP-CFCs) (Dai et al., 2002) (Table 1).

The v-fms gene of the Susan McDonough strain of feline sarcoma virus (SM-FeSV) and feline c-fms differ only by nine scattered point mutations, both in extracellular and intracellular domains, and by a C-terminal truncation in which 50 amino acids of c-fms are replaced by 11 unrelated v-fms-coded residues (Woolford et al., 1988). Mutational analysis has demonstrated that the C-terminal domain of c-Fms possesses negative regulatory capability, whereas activating mutations in codon 301 are required for complete transformation of murine fibroblasts. In mice, proviral integration of the Friend strain of murine leukemia virus (F-MuLV) upstream of the c-fms gene results in greatly increased levels of c-fms transcription and CSF-1R expression, which is associated with the onset of myeloid leukemia in the F-MuLV-infected mice (Gisselbrecht et al., 1987). In human leukemias, c-FMS expression has been reported in a fraction of AML cases, mainly of the monocytic lineage (Ashmun et al., 1989; Rambaldi et al., 1988). Activating point mutations at codons L301 (extracellular domain) and Y969 (C-terminal domain) of CSF-1R have been detected in AML and MDS (Ridge et al., 1990; Tobal et al., 1990). On the other hand, allelic loss of the c-FMS gene occurs in patients with refractory anemia, 5q-syndrome associated myelodysplastic syndromes and AML (Boultwood et al., 1991; McGlynn et al., 1997). These studies do not preclude the role of other genes on the long arm of chromosome 5. Therefore, more elaborate in vivo studies have to assess whether CSF-1R has tumor-promoting and/or tumor-suppressing activity.

Extensive research on the signaling properties of the CSF-1R has provided important insight in the formation of distinct multiprotein signaling complexes upon CSF-1 stimulation (Bourette and Rohrschneider, 2000; Yeung et al., 1998) (Figure 3). In the juxtamembrane (JM) domain of human CSF-1R, Tyr-561 is autophosphorylated upon CSF-1 binding and associates with Src family of tyrosine kinases through their SH2 domain. In mouse CSF-1R, the homologous Tyr-559 site regulates phosphorylation and inactivation of protein phosphatase 2A (PP2A), which is required for CSF-1-mediated differentiation in M1 cells (McMahon et al., 2001). The adaptor proteins Grb2 and Mona interact with activated CSF-1R on Tyr-699, while Tyr-723, another autophosphorylation site located within the kinase insert (KI) domain of CSF-1R, interacts with p85-PI3K and PLCγ2. Src family kinases participate in CSF-1-mediated activation of the PI3K/Akt pathway (Grey et al., 2000; Lee and States, 2000), which is essential for CSF-1-induced cell survival. The suppressor of cytokine signaling (Socs1) associates directly with CSF-1R on Tyr-699 as well as Tyr-723 (Bourette et al., 2001). The third autophosphorylation site located in the KI is Tyr-708, which is required for Stat1 phosphorylation, although the kinase responsible for Stat activation is presently unknown. Mutation of the major autophosphorylation site Tyr-809 in the kinase domain of human CSF-1R severely impairs receptor-mediated mitogenesis in murine fibroblasts (Roussel et al., 1990). However, the equivalent mouse Y807F mutant abrogates CSF-1-induced monocytic differentiation and conversely increases CSF-1-dependent proliferation (Bourette et al., 1995). Although no direct interacting proteins at Tyr-809 have been identified, proteomic analysis reveals altered p45/52Shc phosphorylation with the mouse Y807F CSF-1R mutant, while a non-phosphorylatable form of p45/52Shc prevents CSF-1-mediated macrophage differentiation (Csar et al., 2001).

Besides the molecules that associate directly with the activated CSF-1R, other proteins become also phosphorylated, including multidomain docking protein Gab2 (Liu et al., 2001), inositol 5-phosphatase SHIP1 (Lioubin et al., 1996), Fms interacting protein FMIP (Tamura et al., 1999), tyrosine phosphatases Shp1 and Shp2 (Carlberg and Rohrschneider, 1997; Yeung et al., 1992), non-receptor protein kinase RAFTK (Related Adhesion Focal Tyrosine Kinase) (Hatch et al., 1998), and Cbl (Wang et al., 1996). Cbl functions as a U3 ubiquitin ligase and CSF-1 stimulation induces Cbl-mediated CSF-1R multiubiquitination, which is followed by receptor internalization and degradation (Lee et al., 1999). Furthermore, induction of mitogenic signaling after activation of the CSF-1R results in transcriptional upregulation of the cell cycle regulators Cyclin D1, and Cyclin D2, and transcription factors c-Myc and Ets-2, which is mediated through Src and the Raf/MEK/MAP kinase pathway (Aziz et al., 1999; Dey et al., 2000; Fowles et al., 1998).

c-Kit

The c-KIT gene was identified as the human counterpart of the HZ4 feline sarcoma virus harboring the v-Kit gene, and found to be related to the receptor of the platelet-derived growth factor and CSF-1 (Yarden et al., 1987). Molecular cloning of the loci Dominant white spotting (W) and Steel (Sl) present in natural mouse mutants lead to the identification of the mouse c-Kit receptor and c-Kit ligand (KL) (Chabot et al., 1988; Huang et al., 1990). Loss-of-function mutations at either the W or Sl locus results in reduced thymic cellularity, depletion of erythroid precursors and mast cells, which is associated with macrocytic anemia (Table 1). In addition, there is hypopigmentation, sterility and absence of interstitial cells of Cajal (ICC) in the gut, resulting in reduced gut pacemaker activity. In humans, KIT mutations cause piebaldism, a syndrome resulting in deafness and abnormal skin and hair pigmentation (Fleischman et al., 1991; Giebel and Spritz, 1991). Within the hematopoietic lineage, c-Kit is not only expressed on early hematopoietic stem cells, but also clonogenic myeloid, erythroid, megakaryocytic and dendritic progenitor cells, pro-B and pro-T cells, and mature mast cells (Lyman and Jacobsen, 1998). Two different isoforms of the murine and human c-Kit receptors exist in all of the cells examined, which differ in four amino acids (GNNK) upstream of the transmembrane domain. Ligand-independent constitutive phosphorylation has been observed in the isoform missing these four amino acid residues (Reith et al., 1991). Furthermore, the GNNK- isoform of c-Kit induces more prominent MAPK phosphorylation and has a higher transforming capacity in NIH3T3 cells compared to the GNNK+ isoform (Caruana et al., 1999).

KL is widely expressed during embryogenesis and can be detected on stromal cells, fibroblasts and endothelial cells. KL exists predominantly as a bivalent dimer and can be expressed as membrane-associated or soluble form. KL supports the survival and self-renewal of hematopoietic stem cells and therefore has been alternatively termed stem cell factor (SCF). KL synergizes with erythropoietin in stimulating erythroid progenitor cell proliferation and promotes megakaryocyte progenitor cell growth potential and maturation in combination with other cytokines, especially thrombopoietin (Lyman and Jacobsen, 1998). Furthermore, KL is a potent enhancer of proliferation, survival, chemotaxis and adhesion of mast cells, as well as IgE-mediated degranulation (Vosseller et al., 1997).

Recently, more information has become available on interactions of signaling molecules with specific phosphorylated tyrosine residues located within the human c-Kit receptor (Figure 3). The JM region of c-Kit harboring Tyr-568 and Tyr-570 bind to the Src family members Lyn and Fyn (Linnekin et al., 1997; Price et al., 1997), Csk homologous kinase (CHK) and Shc (Price et al., 1997), while Shp2 interacts with Tyr-568 and Shp1 with Tyr-570 (Kozlowski et al., 1998). Phosphorylated Lyn forms a complex with Tec and p62Dok1, which depends on PI3K activation (van Dijk et al., 2000). In the kinase insert (KI) domain, phosphorylated Tyr-703 interacts with the SH2 domain of Grb2 (Thommes et al., 1999). The adaptor molecules Cbl, Gab1 and Gab2 become tyrosine-phosphorylated and associate with Grb2 following activation of c-Kit (Brizzi et al., 1996b; Nishida et al., 1999). In addition, Socs suppresses the mitogenic potential of c-Kit and associates with c-Kit probably through binding to Grb2 (De Sepulveda et al., 1999).

Mutational analysis has indicated that Tyr-721 in KI domain interacts with p85-PI3K (Serve et al., 1995). PI3K inhibition abolishes Kit-mediated adhesion and cytoskeletal re-arrangement (Vosseller et al., 1997). KL stimulation induces phosphorylation of Crkl, which associates with p85-PI3K and Cbl (Sattler et al., 1997b). PLCγl tyrosine phosphorylation is induced after binding to Tyr-730 (Gommerman et al., 2000), and PLCγ-stimulated Ca2+ influx is critical for KL-dependent cell survival (Gommerman and Berger, 1998). In the C-terminus of c-Kit, autophosphorylation site Tyr-936 interacts with both Grb2 and Grb7 (Thommes et al., 1999). Deletion of the C-terminal domain alleviates Stat5 phosphorylation, but retains Stat1 activation, while absence of the KI domain completely abrogates Stat activation (Brizzi et al., 1999). Other substrates of c-Kit include Vav (Alai et al., 1992), and SHIP2 in association with Shc (Wisniewski et al., 1999).

The biological significance of several c-Kit-activated signaling molecules has been addressed in specific gene knock-out mouse studies. In the absence of the p85α regulatory subunit of PI3K, KL-induced PI3K activation, Akt phosphorylation and proliferation of mast cells is partially inhibited (Lu-Kuo et al., 2000). Cooperative action of PI3K and Src kinases is required to activate Rac and JNK/SAPK pathways and elicit c-Kit-mediated mast cell proliferation and suppression of apoptosis induced by growth factor deprivation and γ-irradiation (Timokhina et al., 1998). Embryonic stem cell-derived mast cells (ESMCs) deficient for MAPK activator MEKK2 display markedly reduced JNK/SAPK kinase activation and cytokine production in response to KL stimulation (Garrington et al., 2000). This is not observed in MEKK1-nullizygous ESMCs, demonstrating clear specificity for MEKK2 in signaling c-Kit-mediated cytokine gene regulation. SHIP−/− bone marrow-derived mast cells (BMMCs) show KL-induced massive degranulation, which is not apparent in SHIP+/+ BMMCs (Huber et al., 1998). This event correlates with higher PtdIns(3,4,5)P3 (PIP3) levels in SHIP1-deficient BMMCs.

Several lines of evidence implicate c-Kit signaling in hematological malignancies. Activating point mutations in c-Kit have predominantly been found in patients with mastocytosis (Longley et al., 1996, 1999; Nagata et al., 1995), a neoplastic disease involving mast cells. The most common mutation is found in the phosphotransferase domain, substituting aspartic acid at codon 816 for valine at the same position (D816V). Activating D816V mutations have also been detected in patients with myeloproliferative syndromes, AML (Beghini et al., 2000; Ning et al., 2001a), and germ cell tumors (Tian et al., 1999). Activation of PI3K and Stat3 contribute to transformation of hematopoietic cells by Asp816 mutant of c-Kit (Chian et al., 2001; Ning et al., 2001b). In addition, a number of in-frame deletion or point mutations in the c-KIT juxtamembrane coding region have been identified in mastocytomas as well as gastrointestinal stromal tumors (GISTs). In a small subset of patients with MPD, there are point mutations in the extracellular domain of c-KIT, causing D52N substitution (Nakata et al., 1995). Furthermore, 63% of AML patients show increased c-Kit expression, while some cases exhibit deletion and insertion mutations in c-Kit extracellular domain involving codon Asp-419 (Gari et al., 1999). Finally, a significant fraction of sinonasal NK/T cell lymphomas carry mutations in codon 825 (Hongyo et al., 2000). Forthcoming studies still need to address the implications of these newly identified c-KIT mutations.

PDGFRβ

The platelet-derived growth factor receptors, PDGFRα and PDGFRβ, are two highly related RTK, showing 85 and 75% identity between the two intracellular kinase domains, but the kinase insert (KI) and the C-terminal tail (CT) regions display only 27 and 28% homology, respectively (Matsui et al., 1989). PDGF has mitogenic activity, primarily for mesenchymal cells, but also promotes migration, differentiation and matrix deposition. PDGF ligand consists of a family of disulphide-bonded dimeric isoforms, PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. Mature PDGF-C and PDGF-D contain an N-terminal region that must be proteolytically removed to enable receptor binding (Bergsten et al., 2001; LaRochelle et al., 2001; Li et al., 2000). PDGF-B and PDGF-D act as agonistic ligands for PDGFRβ, whereas PDGFRα binds all isoforms except PDGF-D. Interestingly, PDGFR not only forms homo- and heterodimers between the α- and β-subunit, but also dimerizes with the epidermal growth factor receptor (EGFR) that can be stimulated by PDGF (Saito et al., 2001).

Interestingly, only the PDGFRβ has been implicated in hematological malignancies, where a substantial fraction of chronic myelomonocytic leukemia (CMML) shows t(5;12)(q33;p13), generating the fusion protein TEL-PDGFRβ (Golub et al., 1994). Other translocation partners of PDGFRβ in CMML are Huntingtin interacting protein 1 (HIP1) and Rabaptin5, corresponding to t(5;7)(q33;q11.2) and t(5;17)(q33;p13), respectively (Magnusson et al., 2001; Ross et al., 1998). CMML has a clinical phenotype similar to CML, but is classified as a MDS characterized by dysplastic monocytosis, variable bone marrow fibrosis, and progression to AML. Furthermore, H4(D10S170) and CEV14 have been found as alternative fusion partners for the transmembrane and tyrosine kinase domains of PDGFRβ in atypical CML (aCML) and acute monocytic leukemia in relapse (Abe et al., 1997; Kulkarni et al., 2000; Schwaller et al., 2001). The TEL pointed (PNT) self-association motif, the HIP1 C-terminal TALIN homology region, Rabaptin5 coiled-coil domains and both CEV14 and H4 leucine zipper domains promote ligand-independent PDGF β-receptor dimerization and autophosphorylation, resulting in a constitutive active tyrosine kinase. It has been demonstrated for most of the translocation-variants that they confer factor-independent growth to Ba/F3 cells, while enforced expression of TEL-PDGFRβ or Rabaptin5-PDGFRβ induces a myeloproliferative disease in a murine BMT model (Magnusson et al., 2001; Tomasson et al., 1999). Dysregulated myelopoiesis and predisposition for the development of myeloid or lymphoid tumors is also evident in CD11a-TEL-PDGFRβ transgenic mice (Ritchie et al., 1999).

The PDGFRβ is expressed on multipotent stem cell, mast cell and myeloid cell lines in addition to myeloblastic leukemias (de Parseval et al., 1993; Foss et al., 2001). Cell populations within the hematopoietic organs known to express PDGF receptors include fibroblasts, early macrophage precursors, macrophages, smooth muscle cells and osteoblasts. T lymphocytes and NK cells also express PDGFRβ, and PDGF can modulate the pattern of T cell cytokines produced in vitro and NK cell cytotoxicity (Daynes et al., 1991; Gersuk et al., 1991). Under unsorted bone marrow culture conditions, PDGF is able to stimulate growth of primitive hematopoietic and erythroid precursors and promote megakaryocytopoiesis, most likely by stimulating mesenchymal cells to cytokine production (Delwiche et al., 1985; Yan et al., 1993; Yang et al., 1995). Targeted disruption of the PDGFRβ gene in mice results in embryonic lethality just prior to birth, displaying hemorrhage, thrombocytopenia, anemia, dilated heart and defects in specialized smooth muscle cells present in vascular capillaries in brain (pericytes) and kidney (mesangial cells) (Lindahl et al., 1998; Soriano, 1994) (Table 1). Studies in reconstituted PDGFRβ-deficient chimeric mice argue that the hematopoietic defects arise secondary to possibly metabolic stress and hypoxia, due to abnormal development of the placental labyrinth (Kaminski et al., 2001).

At present, eleven autophosphorylation sites have been identified in the cytoplasmic part of the PDGF receptor-β (Figure 3). Two autophosphorylation sites in the JM domain (Tyr-579 and Tyr-581) mediate the binding of Src family tyrosine kinases (Mori et al., 1993), the adaptor Shb (Karlsson et al., 1995), and tyrosine phosphorylation of Stat1, Stat3 and Stat5 (Sachsenmaier et al., 1999; Valgeirsdottir et al., 1998), which involves a JAK-independent pathway (Vignais et al., 1996). Even though the Src pathway signals to induce c-myc expression (Barone and Courtneidge, 1995), activation of Src is apparently not required for PDGF-mediated cell cycle entry at the G0/G1 transition. In contrast, Tyr-579 and Tyr-581 appear to be critical for the development of the TEL-PDGFRβ-induced myeloproliferative disease (Tomasson et al., 2000), and are necessary for full activation of Stat5 by TEL-PDGFRβ in Ba/F3 cells (Sternberg et al., 2001). Interestingly, mutating the two tryptophan residues 566 and 593, characteristic for the WW-like domain located in the JM region of H4-PDGFRβ, severely compromises IL-3-independent survival of Ba/F3 cells (Schwaller et al., 2001). Furthermore, Val-536 mutation within the JM domain of the wild type PDGFRβ as well as similar mutations in PDGFRα, CSF-1R and c-Kit, result in constitutive activated tyrosine kinase activity (Irusta and DiMaio, 1998). These data elaborate on a common finding that critical effector molecules important for oncogenic transformation interact with the JM domain of type III RTK.

The KI domain harbors six autophosphorylation sites. The SH2 and PH domain-containing molecules Grb2 and Grb7 both interact with Tyr-716, while Grb7 has also affinity for phosphorylated Tyr-775 (Arvidsson et al., 1994; Yokote et al., 1996). Two autophosphorylation sites Tyr-740 and Tyr-751 bind p85-PI3K (Kashishian et al., 1992). Tyr-751 serves also as a docking site for the adaptor protein Nckα and may compete with p85-PI3K for binding to the PDGFRβ (Nishimura et al., 1993). The autophosphorylation site Tyr-763 and Tyr-771 form binding sites for Shp2 and RasGAP, respectively (Kashishian et al., 1992; Ronnstrand et al., 1999). In addition, Shp2 binds to Tyr-1009 in the C-terminal tail region, which serves as a docking site for Nckβ as well (Chen et al., 2000). PLCγl and adaptor protein APS, which is able to associate with Cbl, interact with Tyr-1021 (Yokouchi et al., 1999). The adaptor protein Shc may interact directly through multiple tyrosine residues or indirectly via association with other tyrosine-phosphorylated proteins (Yokote et al., 1994). In addition, β1 integrin-signaling results in tyrosine phosphorylation of PDGFRβ, which mediates FAK phosphorylation and is dependent on Shp2 recruitment to Tyr-1002 (Qi et al., 1999; Sundberg and Rubin, 1996).

The tyrosine phosphorylation site residing in the catalytic domain (Tyr-857) is necessary for PDGF-mediated increase in kinase activity, but surprisingly not enough for PDGF-dependent autophosphorylation (Baxter et al., 1998). PLCγl and PI3K activation are required for cell proliferation and migration of primary fibroblasts and mesangial cells (Tallquist et al., 2000), and PDGFRβ-mediated monocytic differentiation in myeloid progenitor cells (Alimandi et al., 1997; Kubota et al., 1998). RasGAP suppresses cell migration directed through PDGF-signaling by silencing PLCγl activity (Valius et al., 1995). TEL-PDGFRβ requires engagement of PI3K and PLCγl to promote IL-3-independence in Ba/F3 cells (Sternberg et al., 2001), and induce lymphoid disease efficiently in vivo (Tomasson et al., 2000).

Concluding remarks

Our increasing knowledge of the different signaling components and the various pathways activated by each of the oncogenic tyrosine kinases allows us to obtain a better understanding of the range of biological processes that are controlled by these kinases. In addition, it provides a basis to design rational drugs that may interfere with the tyrosine kinase activity, or inhibit the action of critical signaling proteins that mediate important biological activities of the activated oncogenic tyrosine kinases.

There are many open questions in this field. With the discovery of mutations in FLT3 it is now clear that at least one third of AML patients carry activating alleles of Flt3. Which other tyrosine kinases are activated in the remaining patients? This question applies equally well to the other hematopoietic diseases, especially the broad collection of myeloproliferative disorders, like essential thrombocythemia, agnogenic myeloid metaplasia and Polycythemia vera. Since more translocation breakpoints are being mapped to specific tyrosine kinases, their significance will also extend. Alternatively, it may be worth looking for inactivating mutations in tyrosine phosphatases, since at least in mice, inactivation of Shp1 or SHIP1 is associated with myeloproliferative disorders. Another open question lies in the identification of signaling pathways by tyrosine kinase oncogenes that are either unique or shared, and required for transformation. While it is now possible to generate kinase inhibitors that are selective for each kinase, an alternative strategy might be to target a common pathway required for transformation by all kinases.

Overall, the frequent finding of genetic alterations in tyrosine kinase oncogenes in leukemias and lymphomas may be a cloud with a silver lining. Since there are good targets for drug development and inhibition of tyrosine kinase signaling generally leads to loss of cell viability, many new drugs are likely to be identified in the near future that have significant clinical activity, with modest side effects.

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Acknowledgements

B Scheijen provided the concept, design, collected the data, drafted the paper and gave final approval. JD Griffin drafted the paper and gave final approval. This work was supported by a fellowship of the Dutch Cancer Society (KWF) to B Scheijen.

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Scheijen, B., Griffin, J. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene 21, 3314–3333 (2002). https://doi.org/10.1038/sj.onc.1205317

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Keywords

  • leukemia
  • lymphoma
  • protein tyrosine kinase
  • signal transduction
  • translocation

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