Tyrosine Kinase Oncogenes in Normal Hematopoiesis and Hematological Disease

Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease

Blanca Scheijen1,2 and James D Grin*,1,2

1Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, MA 02115, USA; 2Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

Tyrosine kinase oncogenes are formed as a result of Adaptors do not contain intrinsic catalytic activity but mutations that induce constitutive kinase activity. Many consist of independent functioning interaction modules of these tyrosine kinase oncogenes that are derived from like SH2-domain (mediates binding to phosphotyrosine genes, such as c-Abl, c-Fes, Flt3, c-Fms, c-Kit and residues), SH3-domain (interacts with polyproline-rich PDGFRb, that are normally involved in the regulation of PXXP stretch) or pleckstrin homology (PH) domain hematopoiesis or hematopoietic cell function. Despite (binds to inositol lipids). dierences in structure, normal function, and subcellular The ®rst tyrosine kinase oncogene associated with location, many of the tyrosine kinase oncogenes signal human hematologic disease, Bcr ± Abl, was identi®ed through the same pathways, and typically enhance almost twenty years ago, and there is now evidence for proliferation and prolong viability. They represent involvement of multiple tyrosine kinase oncogenes in excellent potential drug targets, and it is likely that acute and chronic leukemias, lymphomas, and myelo- additional mutations will be identi®ed in other kinases, mas. In each case, the tyrosine kinase activity of the their immediate downstream targets, or in proteins oncogene is constitutively activated by mutations that regulating their function. result in dimerization or clustering, removal of Oncogene (2002) 21, 3314 ± 3333. DOI: 10.1038/sj/ inhibitory domains, or induce the kinase domain to onc/1205317 adopt an activated con®guration. Activated tyrosine kinase oncogenes generally cause enhanced prolifera- Keywords: leukemia; lymphoma; protein tyrosine tion and prolonged viability, but do not typically block kinase; signal transduction; translocation dierentiation. Common signaling pathways are involved in mediating these eects, including activation of phosphotidylinositol 3-kinases (PI3K), the Ras/Raf/ Introduction MAP kinases, phospholipase C-g (PLCg), and Signal transducers and activators of transcription (Stats). On Phosphorylation of tyrosine residues is a conserved the other hand, tyrosine kinase oncogenes seem to be mechanism throughout evolution to transmit activating associated with either lymphoid or myeloid disorders. signals from the cell surface or specialized cellular It is not clear yet if some of the oncogenes have a structures to cytoplasmic proteins and cell nucleus. A predilection for transforming one lineage rather than large family of tyrosine kinases has been identi®ed, another, or if the lineage association is conferred by which largely can be classi®ed as receptor and non- the expression pattern of the translocation fusion receptor tyrosine kinases (Blume-Jensen and Hunter, partner or modi®ed by cooperating oncogenes. 2001). Receptor tyrosine kinases (RTKs) mediate In this review, we will discuss a number of tyrosine cellular responses to a broad array of extracellular kinase oncogenes associated with hematopoietic neo- signals involved in the regulation of cell proliferation, plasia. Both unique and shared features will be migration, dierentiation and survival signaling. Li- emphasized. Their role in normal hematopoiesis as gand binding to the receptor initiates a cascade of well as other relevant biological functions will be events, including receptor homodimerization, activa- considered, and signaling mechanisms described in tion of intrinsic kinase activity, intermolecular tyrosine more detail. trans-phosphorylation, association with signal-transducing proteins and phosphorylation of substrates (Weiss and Schlessinger, 1998). Phosphorylated tyrosine Abl kinase family residues within speci®c sequence contexts serve as high-anity docking sites for Src homology 2 (SH2) c-Abl/ARG domains-containing adaptor and eector molecules. The mammalian Abl family of non-receptor tyrosine kinases consists of c-Abl and ARG (Abl-related gene), *Correspondence: JD Grin; which share 89, 90 and 93% identity in their Src E-mail: james_gri[email protected] homology region (SH) 3, SH2 and tyrosine kinase Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3315 domain, respectively. The overall sequence identity in terminus of c-Abl with intact kinase activity display a the C-terminal half of the proteins is only 29% with similar phenotype, arguing that C-terminal interacting conservation of the proline-rich region and interaction proteins are critical for the biological activity of c-Abl sites for globular (G)- and ®lamentous (F)-actin (Kruh (Schwartzberg et al., 1991). Targeted disruption of the et al., 1990). In contrast to c-Abl, there is no evidence arg gene results in largely normal mice, exhibiting some for DNA-binding activity of ARG, and three NLS behavioral abnormalities, while embryos de®cient for sequences present in c-Abl are not conserved in ARG. both c-Abl and Arg display defective neurulation, Consequently, c-Abl shows both cytoplasmic and increased apoptosis and hemorrhage, and die around nuclear localization, whereas ARG has been detected 10.5 days post coitum (Koleske et al., 1998) (Table 1). predominantly in the cytoplasm (Wang and Kruh, Studies in c-abl7/7/arg7/7 neuroepithelial cells show 1996). The human c-ABL and ARG genes are expressed gross alterations in their actin cytoskeleton. Direct ubiquitously and each gene contains two alternative 5' interaction of Abl family kinases with G- and F-actin exons, generating two variant protein products denoted (Van Etten et al., 1994), as well as cytoskeletal- as type Ia and Ib. The type Ib variant contains a associated proteins Hef1 (Law et al., 1996), amphiphy- consensus sequence for N-terminal myristylation. The sin-like protein 1 (ALP1) (Kadlec and Pendergast, c-Abl proto-oncogene was originally identi®ed as the 1997), Arg binding protein 2 (ArgBP2) (Wang et al., cellular counterpart of v-Abl, encoded by the Abelson 1997), paxillin (Lewis and Schwartz, 1998) and c-Crk II murine leukemia virus. Subsequently, it was demon- (Escalante et al., 2000) may therefore be of great strated that c-Abl is involved in two dierent signi®cance to coordinate cytoskeletal functions. Inter- chromosomal translocations present in human leuke- estingly, recent data show that c-abl7/7/arg7/7 mias, which generate the Bcr-Abl (p185, p210 and ®broblasts display increased motility, and argue that p230) and TEL ± Abl proteins (Andreasson et al., 1997; both c-Abl and Arg negatively regulate cell migration Golub et al., 1996; Papadopoulos et al., 1995). More by disrupting Crk-p130CAS complex formation (Kain recently, TEL ± ARG fusion transcripts have been and Klemke, 2001). identi®ed in acute myeloid leukemias (AML) with a Several lines of evidence suggest a positive role of t(1;12)(q25;p13) translocation (Cazzaniga et al., 1999; c-Abl in cell cycle regulation. In quiescent and G1 cells, Iijima et al., 2000), arguing that both Abl tyrosine nuclear c-Abl is kept in an inactive state by the kinase family members have oncogenic potential. retinoblastoma protein (pRB), which binds to the Mice with a true null mutation for c-Abl show with ATP-binding cleft within the tyrosine kinase domain a variable penetrance neonatal lethality, runted and of c-Abl thereby inhibiting its kinase activity. Phos- dwarf appearance, lymphopenia with increased suscept- phorylation of pRB by cyclin D-Cdk4/6 disrupts the ibility to bacterial infections and defective craniofacial c-Abl/pRB complex at the G1/S transition and results and eye development (Tybulewicz et al., 1991) (Table in the activation of Abl tyrosine kinase during S phase 1). Interestingly, mice containing a truncated C- (Welch and Wang, 1993). In S phase, c-Abl is able to

Table 1 Overview in vivo phenotypes of tyrosine kinase gene-de®cient mice Tyrosine kinase gene(s) Hematological defects Non-hematological phenotypes abl7/7 Hypocellular thymus and spleen, lymphopenia, susceptibility Early postnatal lethality, runted defective craniofacial to bacterial infections, reduced pro-B cells in BM and eye development arg7/7 None Runted at age of 3 weeks Reduced motor skills and mating behavior, abnormal reflexes arg7/7 abl7/7 Not determined Lethal E10.5, defective neurulation, enhanced amount of apoptotic cells in all tissues c-fes7/7 Reduced B cell numbers and more myeloid cells, None compromised innate immunity, diminished adhesion ability of macrophages flt37/7 Less precursor B cells in BM, reduced reconstitution None capacity of the lymphoid lineage csf1r7/7 Decreased monocytes and lymphocyte numbers, Dwarfism, no teeth, osteopetrosis due to less less tissue macrophages, more splenic BFU-E osteoclasts, irregular estrous cycle, defective and HPP-CFCs morphogenesis ductal epithelium, reduced sperm count c-kit7/7 (W/W) Depletion erythroid precursors and mast Hypopigmentation, sterility, absence of cells, reduced thymic cellularity ICC cells in gut

PDGFRb7/7 Secondary hemorrhage, anemia and thrombocytopenia Perinatal lethality, defective mesangial cells in kidney and pericytes in brain capillaries, abnormal placental labyrinth

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3316 contribute to the phosphorylation of the C-terminal damage negatively regulates PI 3-kinase activity (Yuan domain (CTD) of RNA polymerase II, possibly et al., 1997b). Whereas DNA damage activates directly promoting transcription elongation (Baskaran et al., the nuclear form of c-Abl, oxidative stress induces 1993; Duyster et al., 1995). Conversely, c-Abl abro- activation of cytoplasmic c-Abl, which results in the gates pRB-mediated growth arrest in SAOS-2 cells, phosphorylation of protein kinase C d (PKCd) (Sun et which are de®cient in pRb as well as p53 (Welch and al., 2000b). Moreover, c-Abl kinase activity is required Wang, 1995). Abl interacts directly with transcription for oxidative stress-induced mitochondrial cytochrome factors CREB and E2F-1, thereby stimulating their c release and apoptosis (Sun et al., 2000a). Thus, transcriptional activity (Birchenall-Roberts et al., 1995, multiple signaling pathways may contribute to the 1997). Fibroblasts de®cient of c-Abl displayed delayed induction of apoptosis after activation of c-Abl under entry into S-phase upon PDGF stimulation (Plattner et cellular stress-conditions. al., 1999), while c-abl7/7 B lymphocytes show reduced mitogenic response to interleukin (IL)-7 and LPS Bcr-Abl (Hardin et al., 1996). Furthermore, c-Abl contributes to enhanced proliferation of p53-de®cient cells (Whang Chronic myelogenous leukemia (CML) is a clonal et al., 2000). disorder of multipotential hematopoietic stem cells On the other hand, overexpression of c-Abl results in (HSCs), and virtually all cases contain the t(9;22) aG1-arrest that requires its nuclear localizing signals, (q34;q11) translocation characteristic of the Philadelphia SH2 domain and tyrosine kinase activity and is (Ph) chromosome, which is associated with the presence dependent on wild-type p53 and Rb (Sawyers et al., of p210Bcr ± Abl. The p185Bcr ± Abl is characteristic for Ph+ 1994; Wen et al., 1996). c-Abl also has been shown to acute lymphocytic leukemia (ALL), while p230Bcr ± Abl activate programmed cell death independent of pRB has been detected in chronic neutrophilic leukemia. All and p53 (Theis and Roemer, 1998; Yuan et al., 1997a). Bcr ± Abl variants contain elevated tyrosine kinase These eects relate to the ability of c-Abl to induce a activity compared to c-Abl, but among the three forms, Bcr ± Abl G1-arrest and subsequent apoptosis in response to p185 shows the strongest activity. Whereas each cellular genotoxic stress. DNA damage due to ionizing Bcr ± Abl protein harbors the coiled-coil (CC) oligomer- radiation (IR) or cytotoxic drugs leads to activation of ization domain (amino acids 1 ± 63) and the serine/ c-Abl, which is dependent on DNA-dependent protein threonine kinase domain (amino acids 64 ± 414) in the kinase (DNA-PK) and ataxia telangiectasia mutated Bcr region, the Dbl/CDC24 guanine nucleotide ex- (ATM) kinase (Baskaran et al., 1997; Shafman et al., change factor (GEF) homology (Dbl) domain and 1997). Subsequently, c-Abl interacts with p53 and pleckstrin homology (PH) domain (amino acids 734 ± enhances p53-mediated transcription and growth sup- 866) are absent in p185Bcr ± Abl. The CC oligomerization pression (Yuan et al., 1996). In addition c-Abl domain is critical for transformation and induces promotes nuclear accumulation of p53 by preventing tetramerization of Bcr ± Abl that is required for the ubiquitination and nuclear export of p53 by Mdm2 constitutive activation of the tyrosine kinase of Bcr ± Abl (Sionov et al., 2001). Furthermore, in response to DNA (McWhirter et al., 1993). Additional domains within Bcr damage c-Abl phosphorylates Rad51, prohibiting its that are relevant for ecient oncogenic transformation function in DNA double-strand break repair and by p210Bcr ± Abl include two SH2-binding regions (amino genetic recombination (Chen et al., 1999; Yuan et al., acids 176 ± 242 and amino acids 298 ± 413) (Pendergast et 1998), and phosphorylates the p53-related protein p73, al., 1991), and Dbl domain (Kin et al., 2001). where c-Abl stimulates its transcriptional activity and Transforming capacity of Bcr ± Abl is weak in Rat1 promotes p73 protein stability (Agami et al., 1999; ®broblasts, but is evident in hematopoietic cells and Gong et al., 1999; Yuan et al., 1999). Most likely, p53 requires the presence of a functional protein kinase and p73 represent distinct eectors activated after domain. Activation of Ras, Raf, PI3K, and JNK/SAPK genotoxic stress, since targeted gene-inactivation experi- signaling pathways (Dickens et al., 1997; Sawyers et al., ments reveal non-overlapping functions for both genes. 1995, Skorski et al., 1995a,b, 1997), as well as Activation of c-Abl upon DNA damage is also transcriptional activation of NF-kB, c-Jun and c-Myc reported to contribute to the induction of Jun kinase are required for Bcr ± Abl-induced transformation (JNK/SAPK) and p35 MAPK pathways, which are (Raitano et al., 1995; Reuther et al., 1998; Sawyers et involved in the induction of apoptosis. Cells de®cient al., 1992). Cooperation between multiple signaling in c-Abl fail to activate JNK/SAPK and p38 MAPK pathways, including Ras and PI3K, is required for the after treatment with certain DNA-damaging agents full oncogenic activities of Bcr ± Abl (Sonoyama et al., (Kharbanda et al., 1995; Pandey et al., 1996), which 2002). Additionally, Stat5 is constitutively activated by correlates with the ability of c-Abl to bind and tyrosine phosphorylation in Bcr ± Abl-transformed cells stimulate the activity of the upstream eectors MEK (Carlesso et al., 1996; Ilaria and Van Etten, 1996), which kinase 1 (MEKK1) and hematopoietic progenitor is required for their growth and viability (Gesbert and kinase 1 (HPK1) in response to genotoxic stress (Ito Grin, 2000; Sillaber et al., 2000). However, myeloid et al., 2001; Kharbanda et al., 2000). Additionally, it cells de®cient in Stat5a/b display unaltered transforma- has been demonstrated that the p85 subunit of PI3K tion eciency by p210Bcr ± Abl (Sexl et al., 2000). (p85-PI3K) interacts with c-Abl, where tyrosine Bcr ± Abl inhibits apoptosis in cells exposed to DNA phosphorylation of p85-PI3K in response to DNA damage, cytokine deprivation and Fas activation,

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3317 which involves several mechanisms blocking mitochon- was identi®ed as one of the major tyrosine phosphory- drial release of cytochrome c and procaspase-3 lated proteins in CML neutrophils and Bcr ± Abl- activation (Amarante-Mendes et al., 1998b; Dubrez et expressing cell lines (Oda et al., 1994). Abl as well as al., 1998). These include Bad phosphorylation (Neshat the guanine nucleotide exchange factors mSOS and et al., 2000), and induction of Bcl2 and Bcl-xL levels C3G interact with Crkl-SH3 domains (Feller et al., (Amarante-Mendes et al., 1998a; Sanchez-Garcia and 1995). On the other hand, the SH2 domain of Crkl Grutz, 1995). Activation of Stat5 and inhibition of serves as a docking site for Cbl (de Jong et al., 1995), caspase-3 cleavage by Bcr ± Abl result in overexpression SHIP1 (Sattler et al., 2001), activator of the JNK/ of Rad51 and its paralogs, leading to increased drug SAPK pathway GCKR (Germinal Center Kinase resistance (Slupianek et al., 2001b). Furthermore, Bcr ± Related) (Shi et al., 2000), cytoskeletal-associated Abl-mediated down-regulation of p27Kip1 levels may proteins p130CAS (Salgia et al., 1996a), Hef1/Cas-L contribute to enhanced survival signaling in hemato- (de Jong et al., 1997), and paxillin (Salgia et al., 1995). poietic cells (Gesbert et al., 2000; Jonuleit et al., 2000; The abl interactor (Abi) proteins (Dai and Pendergast, Parada et al., 2001). 1995; Shi et al., 1995), which have been implicated in Besides its established role in preventing pro- Rac-dependent cytoskeletal reorganization, provide grammed cell death, the eects of Bcr ± Abl on alternative ways for Bcr ± Abl to control cytoskeletal hematopoietic cell dierentiation are less well de®ned. function. DokL (Cong et al., 1999), Grb10 (Bai et al., Bcr ± Abl increases the myeloid cell compartment after 1998b), Gads (Liu and McGlade, 1998) and Nckb retroviral transduction of murine bone marrow, but (Coutinho et al., 2000) are additional adaptor proteins does not alter the fundamental potential of HSC to that associate with Bcr ± Abl, while PLCgl (Gotoh et dierentiate along lymphoid, myeloid or erythroid al., 1994), Vav (Matsuguchi et al., 1995), c-Fes (Ernst lineages (Li et al., 1999). This is consistent with the et al., 1994), Src kinases Hck and Lyn (Danhauser- clinical phenotype of stable phase human CML. Riedl et al., 1996) and Rin1 (Afar et al., 1997) are However, Bcr ± Abl can prevent G-CSF-mediated tyrosine phosphorylated in cells expressing Bcr ± Abl. dierentiation of the myeloid precursor cell line 32D, It has been a dicult challenge to recapitulate the by inducing the expression of the RNA-binding protein p210Bcr ± Abl-induced chronic myeloid disease in a mouse hnRNP-E2, thereby suppressing C/EBPa translation model (Wong and Witte, 2001). Transgene-driven and consequently transcriptional activation of granu- expression of Bcr ± Abl has predominantly resulted in locyte colony-stimulating factor receptor (G-CSF-R) lymphoid malignancies (Honda et al., 1995; Voncken et (Perrotti et al., 2002). al., 1995), whereas in Tec-p210Bcr ± Abl transgenic mice Bcr ± Abl is constitutively phosphorylated on many an overt myeloproliferative disease (MPD) occurs only tyrosine residues, of which only a few have been after a long latency (Honda et al., 1998). A murine mapped, including Tyr-177 within the Bcr region and bone marrow retroviral transduction/transplantation Tyr-1294 in the Abl kinase domain. Tyr-177 serves as a (BMT)-based approach has proven to be more docking site for adaptor protein Grb2, and this successful (Pear et al., 1998; Zhang and Ren, 1998). interaction is critical for Bcr ± Abl-induced transforma- Whereas p185, p210 and p230 are associated with tion (Pendergast et al., 1993). Grb2 recruits the Ras distinct clinical entities in humans, all three Bcr ± Abl GTP/GDP exchange factor mSOS (Egan et al., 1993) variants are equally potent in inducing a CML-like and Bcr ± Abl-mediated phosphorylation of Grb2 disease in transplanted mice (Li et al., 1999). Down inhibits binding to mSOS (Li et al., 2001). Grb2 also regulation of transcription factor Interferon Consensus associates with tyrosine phosphatase Shp2 and p85 Sequence Binding Protein (ICSBP) is essential for regulatory subunit of PI3K (p85-PI3K) (Tauchi et al., induction of MPD by Bcr ± Abl (Hao and Ren, 1997). Shp2 on its turn can form a complex with dual 2000). In the absence of the proline-rich stretch, the adaptor/inositol 5-phosphatase SHIP1 (Sattler et al., SH2 or SH3 domain, Bcr ± Abl is not compromised in 1997a). Adaptor molecules Shc and Grap may act as its ability to elicit a MPD, only the latency of the alternative pathways from Bcr ± Abl to Ras (Feng et disease is extended (Gross et al., 1999; Roumiantsev et al., 1996; Puil et al., 1994; Tauchi et al., 1994). On the al., 2001; Zhang et al., 2001b). In contrast, deletion of other hand, Ras GTPase activating protein (RasGAP) both the SH3-domain and proline-rich stretch, or the interacts with the highly phosphorylated protein N-terminal CC domain, or mutation of the Grb2 p62Dok1 (Carpino et al., 1997; Yamanashi and binding site Tyr-177 severely impair the development Baltimore, 1997), or its homolog p56Dok2 (Di Cristofa- of a CML-like disease (Dai et al., 2001; Zhang et al., no et al., 1998), and tyrosine phosphorylation of 2001a), suggesting that Bcr as well as Abl sequences p62Dok1 by Bcr ± Abl inhibits RasGAP activity. play an important role in the onset of chronic myeloid Apart from Grb2, also Cbl and Crkl serve as leukemia. important intermediate signaling proteins for linking Bcr ± Abl to the major eector pathways (Figure 1). Cbl, the cellular homolog of the v-Cbl oncoprotein, ALK binds to the Abl ± SH2 domain and recruits p85-PI3K (Sattler et al., 1996). Cbl forms a complex with Grb2 Anaplastic lymphoma kinase (ALK) is an orphan (Jain et al., 1997) and associates with focal adhesion receptor tyrosine kinase, highly related to the leukocyte proteins paxillin and talin (Salgia et al., 1996b). Crkl tyrosine kinase (LTK), whose expression is normally

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3318

Figure 1 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 ®lamentous (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

restricted to speci®c regions of the central and peripheral et al., 1998). Although the NPM region is essential for nervous system (Iwahara et al., 1997; Morris et al., 1997). oncogenic transformation by NPM ± ALK, nuclear Initially, ALK was found as an oncogene tyrosine kinase localization, which occurs through heterodimerization fused to nucleolar protein B23/nucleophosmin (NPM) with NPM and its associated shuttling activity, is not (Morris et al., 1994; Shiota et al., 1994), a ubiquitously required for tumorigenesis (Bischof et al., 1997; Mason expressed RNA-binding nucleolar phosphoprotein cap- et al., 1998). NPM ± ALK is able to associate with the able of shuttling newly synthesized proteins between adaptor proteins IRS-1 (Tyr-156), Shc (Tyr-567), Grb2, nucleolus and cytoplasm (Borer et al., 1989). The Grb7, Grb10, Gab2, and Crkl (Bai et al., 1998a, 2000; chimeric gene NPM ± ALK is produced by the chromo- Fujimoto et al., 1996). Interaction of NPM ± ALK with somal translocation t(2;5)(p23;q35) (Bitter et al., 1990; PLCgl at Tyr-664 is critical for IL-3-independent Mason et al., 1990; Morris et al., 1994; Wellmann et al., proliferation of Ba/F3 lymphocytes and transformation 1995), and is present in approximately 30 to 50% of of Rat1 cells (Bai et al., 1998a), whereas activation of anaplastic large-cell lymphomas (ALCL), which forms a PI3K, Akt and Stat5 are required for growth factor- subgroup of non-Hodgkin lymphoma that often express independent survival and transformation (Bai et al., the membrane antigen CD30 and mainly consists of T/ 2000; Nieborowska-Skorska et al., 2001; Slupianek et null cells (Stein et al., 2000). Fusion of the N-terminal al., 2001a). Furthermore, NPM ± ALK expressing T domain of NPM (amino acids 1 ± 117) to the cytoplasmic cell lines display multilevel Stat3 activation (Zhang et region of the ALK receptor (amino acids 1059 ± 1620) al., 2002), and PI3K- and PLCg-independent drug- generates an 80 kD NPM ± ALK fusion protein which resistance (Greenland et al., 2001). forms homodimers, resulting in the constitutive activa- Several reports showed that 15 to 28% of ALK+ tion of the catalytic ALK tyrosine kinase domain lymphomas were negative for the t(2;5) translocation, (Bischof et al., 1997; Fujimoto et al., 1996). suggesting the existence of variant X-ALK fusion NPM ± ALK is capable of transforming rodent proteins (Benharroch et al., 1998; Falini et al., 1998, ®broblasts (Bai et al., 1998a; Bischof et al., 1997; 1999; Pulford et al., 1999). Indeed, various studies have Fujimoto et al., 1996), primary mouse bone marrow identi®ed alternative fusion partners of the ALK cells (Bai et al., 2000) and induces B cell lymphomas in cytoplasmic domain in ALCL (Figure 2). These include mice after retroviral gene transfer (Kuefer et al., 1997). the nonmuscle tropomyosins TPM3 and TPM4 at Immunostaining for ALK in ALCL tumors and t(1;2)(q21;p23) and t(2;19)(p23;p13.1) respectively (La- transfected cell lines reveals both nuclear and cyto- mant et al., 1999; Meech et al., 2001; Siebert et al., plasmic localization of NPM ± ALK (Bischof et al., 1999), two dierent variants of TFG (tropomyosin 1997; Falini et al., 1999; Mason et al., 1998; Wlodarska receptor kinase-fused gene) at t(2;3)(p23;q21) (Hernan-

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3319

Figure 2 Schematic representation of the various anaplastic lymphoma kinase (ALK) fusion proteins and their characteristic features in Alk+ anaplastic large cell lymphomas (ALCL) and in¯ammatory myo®broblastic 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 myo®broblastic spindle cells admixed with in¯ammatory cells (lymphocytes, eosinophiles, and plasma cells) and collagen ®bers. 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 identi®ed partner of ALK in ALCL. TFG ± ALK chimeric transcripts may consist of two dierent TFG variants, generating two distinct fusion proteins. The asterisk indicates that the reported translocation involving RanBP2 has not yet been cytogenetically con®rmed dez et al., 1999), the clathrin heavy chain gene CLTC abdomen of children and adolescents (Con et al., (and not CLTCL) at t(2;17)(p23;q23) (Morris et al., 1998). Immunohistochemistry shows that 60% of IMTs 2001; Touriol et al., 2000), the ERM protein moesin are positive for ALK expression (Cook et al., 2001). (MSN) at t(2;X)(p23;q11-12) (Tort et al., 2001), and Although it has been suggested that IMTs are of the bifunctional enzyme ATIC (5-aminoimidazole-4- nonneoplastic origin, the identi®cation of clonal carboxamide-1-beta-D-ribonucleotide transformylase/ chromsomal aberrations involving TPM3 ± ALK, inosine monophosphate cyclohydrolase) at inversion TPM4 ± ALK, CLTC ± ALK and RanBP2 ± ALK gene (2)(p23;q35) (Colleoni et al., 2000; Ma et al., 2000; fusion transcripts in IMT argue for a neoplastic Trinei et al., 2000). In contrast to NPM ± ALK, all process (Bridge et al., 2001; Lawrence et al., 2000; variant fusion proteins are absent from the nucleus and Morris et al., 2001). ALK may therefore not be a are localized to cytoplasm or plasma membrane, lineage speci®c oncogene tyrosine kinase, but is able to supporting previous ®ndings that the oncogenic transform dierent mesenchymal cell types. potential of ALK is not dependent on its nuclear localization. However, similar to NPM, all other variant fusion proteins contain speci®c multimerization c-Fes/Fps regions, and each of them is capable of eliciting ALK tyrosine kinase activation. The c-Fes/Fps proto-oncogene is the mammalian Besides its prominent role in CD30+ ALCL, there is equivalent of the v-fes transforming oncogene asso- considerable amount of data to suggest that constitu- ciated with the Gardner-Arnstein and Snyder-Theilen tive activation of the ALK kinase is also involved in strains of feline sarcoma virus and the v-fps oncogenes the pathogenesis of an unrelated disease, called of Fujinami and PRC-type chicken sarcoma viruses in¯ammatory myo®broblastic tumors (IMT) (Con et (Groen et al., 1983). Like c-Abl,c-Fes encodes for a al., 2001; Grin et al., 1999). IMTs consist of spindle non-receptor tyrosine kinase and contains an N- shaped myo®broblasts with a pseudosarcomatous terminal domain with two predicted coiled-coil (CC) in¯ammatory appearance and arise mostly in the regions involved in oligomerization (residues 1 to 450),

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3320 a central SH2 domain and a carboxy-terminal tyrosine Identi®ed substrates for the cellular Fes kinase kinase domain (Roebroek et al., 1985). However, Fes include RasGAP (Hjermstad et al., 1993), Stat3 lacks a negative regulatory tyrosine phosphorylation (Nelson et al., 1998), Cas (Jucker et al., 1997), IRS-2 site at the carboxy-terminal end, it has no SH3 domain (Jiang et al., 2001), and Bcr (Maru et al., 1995). and is not modi®ed by N-terminal myristylation. All Tyrosine phosphorylation of Bcr on Tyr-177 and Tyr- three structural domains of p95c-Fes have the potential 246 by Fes suppresses Bcr serine/threonone kinase to regulate the rather constrained Fes kinase activity in activity toward 14-3-3 protein BAP-1 (Li and Smith- vivo. Deletion of the SH2 domain inhibits Fes gall, 1996), but induces association with Grb2/mSOS, autophosphorylation on Tyr-713 and Tyr-811, provid- the Ras guanine nucleotide exchange factor complex ing evidence for intermolecular trans-phosphorylation, (Maru et al., 1995). Signaling downstream of the IL- and mutagenesis of the Tyr-713 autophosporylation 4Ra involves Fes-mediated PI3K recruitment and site within the kinase domain greatly diminishes kinase activation of p70S6K but not Akt kinase (Jiang et al., activity (Hjermstad et al., 1993; Rogers et al., 1996). 2001). Ras activity as well as activation of the Rho Finally, mutation or deletion of the ®rst CC domain family of small G proteins Rac and Cdc42 are required activates Fes tyrosine activity, which is signi®cantly for ®broblast transformation of myristylated c-Fes (Li abrogated by a point mutation in the second CC and Smithgall, 1998). domain (Cheng et al., 1999, 2001). Human myeloid leukemia cell lines, such as HL-60, In developing and adult tissues, c-Fes mRNA KG-1, TF-1, THP-1 and U937 that have retained the transcripts are mainly evident in hematopoietic pro- capacity to undergo dierentiation all express c-Fes genitor cells and mature granulocytes and monocytes, mRNA levels. In addition, Fes protein levels can be but can also be detected in vascular endothelial cells, detected in some human and mouse B and T cell lines chondrocytes, Purkinje cells, neuronal cells in the (Izuhara et al., 1994; MacDonald et al., 1985). molecular layer of the cerebellum and some epithelial Expression of the p93c-Fes protein is especially high in cell types (Haigh et al., 1996). Fes tyrosine kinase has acute and chronic myeloid leukemias (Smithgall et al., been found to localize in cytoplasmic as well as in 1991), although this may merely re¯ect the myeloid (peri-)nuclear and plasma membrane fractions (Feld- component of these malignancies. An aberrant trun- man et al., 1983; Yates et al., 1995), although more cated c-Fes transcript is expressed in various lympho- recent data demonstrate p93c-Fes protein localization ma and lymphoid leukemia cell lines, but there is no within the Golgi network and cytoplasmic vesicles, direct evidence that the encoded 17 kD protein may arguing for a role of Fes in vesicular tracking result in activation of full length Fes (Jucker et al., (Zirngibl et al., 2001). Release of Fes transforming 1992). Enforced expression of v-fps renders FDC-P1 activity occurs through the cloning of an additional cells IL-3 independent (Meckling-Gill et al., 1992) and myristylation signal sequence at the N-terminus, which induces T cell lymphomas, (neuro-)®brosarcomas, targets Fes to membranes (Greer et al., 1994), or Src- hemangiomas and angiosarcomas in transgenic mice SH2 domain substitution with concomitant localization (Yee et al., 1989), whereas mice transgenic for at focal adhesions (Rogers et al., 2000). myristylated c-Fes develop multifocal hemangiomas, Fes seems to be activated by several distinct cytokine but display no susceptibility for the development of receptor subunits that lack intrinsic tyrosine kinase hematopoietic tumors (Greer et al., 1994). activity themselves. The gp130 signal-transducing On the contrary, several reports show that c-fes subunit forms a part of the IL-6-related cytokine expression correlates with induction of myeloid dier- subfamily receptors, and is associated with Fes in the entiation (Smithgall et al., 1988; Yu and Glazer, 1987). absence of receptor stimulation, while Fes becomes In fact, c-Fes overexpression restores the capability of tyrosine phosphorylated after IL-6 stimulation (Matsu- K562 leukemic cells to undergo myeloid dierentiation da et al., 1995). Fes interacts also with the IL-4Ra (Yu et al., 1989). Inhibition of Fes protein levels by subunit and becomes tyrosine phosphorylated by JAK1 antisense oligodeoxynucleotides in HL60 prevents upon ligand binding (Izuhara et al., 1994; Jiang et al., granulocytic and macrophage dierentiation (Ferrari 2001). The involvement of Fes in mediating signals et al., 1994; Manfredini et al., 1993, 1997). However, 7/7 downstream of the common b (bc) subunit, which is studies in c-fes mice show that Fes is dispensable part of the IL-3/IL-5/GM-CSF receptor complex, and for normal development of the myeloid lineage. The the erythropoietin (EPO) receptor are however more only functional defect in Fes-de®cient mice relates to controversial. It has been reported that Fes associates the decreased adhesion capacity of c-fes7/7 macro- with bc in vitro (Rao and Mufson, 1995), and becomes phages, which may explain the compromised innate phosphorylated and activated in response to IL-3 and immunity observed in these animals (Hackenmiller et GM-CSF stimulation (Brizzi et al., 1996a; Hanazono et al., 2000) (Table 1). While reduced numbers of B al., 1993a; Park et al., 1998), but this could not be lymphocytes are observed at all stages of B cell con®rmed in other studies (Anderson and Jorgensen, development, the myeloid lineage is overrepresented 1995; Linnekin et al., 1995; Quelle et al., 1994). in bone marrow and peripheral hematopoietic tissues. Similarly, in TF-1 cells EPO induces Fes tyrosine This relates to enhanced Stat3 activation after IL-6 phosphorylation and activation (Hanazono et al., stimulation, and increased Stat3 and Stat5 activation 1993b), but this has been challenged by others upon GM ± CSF stimulation in c-fes7/7 macrophages. (Witthuhn et al., 1993). No dierences are observed with IL-3 and IL-10, and

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3321 c-fes7/7 neutrophils display normal patterns of activa- et al., 2002). FL stimulates proliferation and colony tion. These data argue that endogenous Fes acts formation of the vast majority of adult and pediatric primarily in the monocytic lineage as a negative AML-leukemic cells and promotes their survival, regulator of Stat3 and Stat5 activation, probably by although to a variable extent (Lisovsky et al., 1996; direct sequestering of Stats and competing with the McKenna et al., 1996; Piacibello et al., 2000). more potent activator Jak3 for Stat phosphorylation. As predicted from the Flt3 expression pattern, FL potently enhances the colony-stimulating activity on hematopoietic progenitor cells in synergy with G-CSF, Flt3 GM ± CSF, M-CSF, IL-3, IL-6, IL-11, IL-12 or KL. FL can also support proliferation of murine B cell The murine Flt3/Flk-2 receptor was cloned by low progenitor cells committed to the erythrocyte, mega- stringency hybridization with a c-fms DNA fragment karyocyte, eosinophil, or mast cell lineages (Hirayama as a probe (fms-like tyrosine kinase 3) (Rosnet et al., et al., 1995; Hudak et al., 1995; Jacobsen et al., 1995). 1991), and by degenerate PCR on a fetal liver cDNA No restrictions in species speci®city has been observed library based on the conserved kinase domain of for the eects of FL, as murine and human FL are tyrosine kinase receptors (fetal liver kinase 2) (Mat- active on cells from both species. In vivo administration thews et al., 1991). The human homologue, alterna- of FL alone increases granulocytic-monocytic (GM) tively termed stem cell tyrosine kinase-1 (STK-1), and multipotent granulocytic-erythroid-monocytic- encodes a protein of 993 amino acids with 85% megakaryocytic (GEMM) colonies fourfold and seven- identity and 92% similarity with the corresponding fold, respectively (Brasel et al., 1996). FL is also able to mouse Flt3 protein (Rosnet et al., 1993; Small et al., promote the survival of late myeloid progenitors 1994). The Flt3 receptor has the same general structure (Nicholls et al., 1999). FL enhances the production of as four other tyrosine kinase receptors that comprise dendritic cells (DC) from CD34 BM progenitor cells in the type III receptor tyrosine kinases (RTK) subfamily: combination with GM ± CSF, TNF and IL-4. In vivo c-Fms, the receptor for colony-stimulating factor-1 treatment of mice with FL results in a dramatic (CSF-1), c-Kit, and both of the receptors for platelet- increase of DC in all primary and secondary lymphoid derived growth factor (PDGFRa and PDGFRb). Each tissues (Maraskovsky et al., 1996), and in humans it of these receptor molecules has ®ve immunoglobulin- induces both CD11c+ and CD11c7 subsets (Maras- like (Ig) domains in the extracellular region and a split kovsky et al., 2000; Pulendran et al., 2000). Since DC catalytic domain in the intracellular part of the are the most ecient antigen presenting cells (APC) for receptor. T cells, FL administration has been shown to inhibit The ligand for the Flt3 receptor (FL) encodes a type tumor growth and promote tumor regression and 1 transmembrane protein, but soluble and membrane- immunization in experimental cancer models (Chen et bound isoforms can be generated as a result of al., 1997; Lynch et al., 1997). alternative splicing of mRNAs (Hannum et al., 1994; The phosphorylated cytoplasmic domain of murine Lyman et al., 1993). The natural occurring soluble FL Flt3 transduces activation signals through direct protein exists of a 65 kD nondisul®de-linked homo- interaction with Grb2 and the p85 subunit of PI3K, dimeric glycoprotein comprised of 30 kD subunits, and phosphorylation of SHIP, Shc, Vav, RasGAP and each containing up to 12 kD of N- and O-linked sugars PLCg (Dosil et al., 1993; Marchetto et al., 1999; (McClanahan et al., 1996). FL is structurally similar to Rottapel et al., 1994). Although no speci®c Tyr Kit Ligand (KL) and M-CSF, and the crystal structure residues have been mapped which mediate the of FL shows the presence of a four-helix bundle fold interaction with speci®c signal-transducing molecules, with the two monomers forming an antiparallel dimer FL stimulation on human Flt3 receptor results in direct (Savvides et al., 2000). FL mRNA transcripts are association with Grb2 and Socs1, phosphorylation of present in a wide variety of human and mouse tissues, Cbl, CblB, Shc, SHIP, Shp2, Gab1, Gab2, Stat5a and including spleen, thymus, heart, lung, liver and kidney. activation of the MAP kinase pathway (Lavagna- In contrast, Flt3 receptor is preferentially expressed in Sevenier et al., 1998a,b; Zhang and Broxmeyer, 2000; primitive CD34+ hematopoietic stem cells, pro-B cells Zhang et al., 2000) (Figure 3). In contrast to murine and immature CD47CD87 thymocytes in addition to Flt3, human Flt3 has no potential SH2-domain binding gonads, placenta and brain. FL mRNAs are found in site for p85-PI3K in the carboxyl terminus, nor does most hematopoietic cell lines, whereas Flt3 is primarily p85 seem to be phosphorylated upon FL binding expressed in pre-B, monocytic and myeloid cell lines (Zhang and Broxmeyer, 1999). Instead, p85-PI3K has (Brasel et al., 1995; Meierho et al., 1995). In primary been found associated with tyrosine phosphorylated tumors, increased expression of Flt3 is detected on Shp2, SHIP, Gab1, Cbl and CblB. The signi®cance of most leukemic samples of AML and B-ALL, but Stat5a in Flt3 signaling is illustrated by the fact that generally only at low levels on T-ALL (Birg et al., only Stat5a7/7, and not Stat5b7/7, bone marrow 1992; Carow et al., 1996). Interestingly, Flt3 is the progenitor cells are unresponsive to FL-mediated most dierentially expressed gene that distinguishes a proliferative eects (Zhang et al., 2000). subset of human acute leukemias involving the mixed- Detailed analysis in ¯t37/7 mice has indicated that lineage leukemia gene (MLL) (high expression) from mainly primitive B lymphoid progenitor cells are conventional B-precursor ALL and AML (Armstrong aected in the absence of Flt3 expression (Mackar-

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3322

Figure 3 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 ®ve 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 eector molecules. Dashed arrows suggest substrate phosphorylation through unidenti®ed 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)

ehtschian et al., 1995) (Table 1). However, normal of childhood AML cases, in 3 ± 5% of MDS, 20% of numbers of functional B cells are present in the acute promyelocytic leukemia and 3% of pediatric periphery, and total composition and cell numbers of ALL, expressing myeloid antigens (Kiyoi et al., 1997; hematopoietic organs and peripheral blood are indis- Meshinchi et al., 2001; Rombouts et al., 2000; Xu et tinguishable between ¯t37/7 and wild-type mice. al., 1999). The presence of ITD in Flt3 correlates with Although the Flt3 receptor is expressed on murine a poor outcome in adult and pediatric AML. Disease- and human cell populations enriched for hematopoietic free and overall survival is even more inferior in Flt3- stem and progenitor cells, the population of multi- ITD cases lacking the wild type Flt3 allele (Whitman potential and myeloid colony-forming progenitors is et al., 2001). The length of the ID is variable, but the not aected in ¯t37/7 mice. Only competitive duplicated sequence is selected for in-frame fusions, repopulation experiments reveal a signi®cant defect of and mostly involves the Tyr-rich stretch 587-NEY- Flt3-de®cient stem cells, where reconstitution of the FYVDFREYEYD-560 located in exon 11. The Flt3- hematopoietic system is less ecient in comparison to ITD receptor activates Stat5 and the MAP kinase wild-type stem cells, especially of the lymphoid lineage. pathway and promotes increased phosphorylation of In contrast, ¯t3L7/7 mice display an overt reduction in Akt. Interestingly, in a murine BMT assay, Flt3-ITD, leukocyte counts of bone marrow, spleen, lymph nodes but not wild-type Flt3, even with high expression and peripheral blood (McKenna et al., 2000). Absolute levels, induces a myeloproliferative phenotype (Kelly numbers of CFU-GM are slightly reduced, whereas B- et al., 2002). Remarkably, elongation of the JM cell precursors show a signi®cant reduction, similar to portion rather than introduction of new tyrosine ¯t3 receptor-de®cient mice. In addition, ¯t3L7/7 mice residues generates ligand-independent dimerized ver- have decreased numbers of myeloid-related sions of Flt3. However, some tandem duplications in (CD8a7CD11chi) and lymphoid-related (CD8a+CD11- Flt3 show no constitutive autophosphorylation of Flt3 chi) DC and are de®cient in NK cells. At present it is (Fenski et al., 2000). Recently, several kinds of unclear whether these distinct phenotypes re¯ect true missense mutations at Asp-835 located in the activa- dierences between ¯t37/7 and ¯t3L7/7 mice or relates tion loop of the second tyrosine kinase domain of Flt3 to mice strain variations. have been found in 7% of AML cases and 3% of One important indication implicating Flt3-mediated MDS and ALL cases (Abu-Duhier et al., 2001; signaling in the pathogenesis of myeloid leukemia has Yamamoto et al., 2001). All D835-mutant Flt3 been the identi®cation of an internal tandem duplica- variants induce constitutive tyrosine phosphorylation tion (ITD) in the juxtamembrane (JM) domain of and confer IL-3-independence in 32D cells. D835 FLT3 in AML (Nakao et al., 1996). Subsequent mutations occur independently of Flt3/ITD (Yama- studies have shown that Flt3 tandem duplications are moto et al., 2001), arguing that each variant may present in 17 ± 27% of de novo adult AML, 14 ± 17% contribute to the pathogenesis of acute leukemia.

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3323 c-Fms/CSF-1R Activating point mutations at codons L301 (extracellular domain) and Y969 (C-terminal domain) of CSF-1R have The c-fms proto-oncogene encodes for the receptor of been detected in AML and MDS (Ridge et al., 1990; colony-stimulating factor-1 (CSF-1), also called macro- Tobal et al., 1990). On the other hand, allelic loss of the phage colony-stimulating factor (M-CSF), which is a c-FMS gene occurs in patients with refractory anemia, lineage-speci®c cytokine stimulating proliferation and 5q-syndrome associated myelodysplastic syndromes and dierentiation of monocyte progenitors and supporting AML (Boultwood et al., 1991; McGlynn et al., 1997). the survival of mature macrophages (Stanley et al., These studies do not preclude the role of other genes on 1983). The CSF-1R is a transmembrane glycoprotein of the long arm of chromosome 5. Therefore, more 150 kD and belongs to the class III family of intrinsic elaborate in vivo studies have to assess whether CSF- tyrosine kinase growth factor receptors. The human c- 1R has tumor-promoting and/or tumor-suppressing FMS gene is located on chromosome 5q33.3 and is activity. expressed in cells of the monocyte/macrophage lineage, Extensive research on the signaling properties of the cm+ pre-B cells, placental trophoblasts, CNS neurons CSF-1R has provided important insight in the and microglial cells (Arceci et al., 1989; Brosnan et al., formation of distinct multiprotein signaling complexes 1993; Lu and Osmond, 2001). The importance of CSF- upon CSF-1 stimulation (Bourette and Rohrschneider, 1 in the regulation of the mononuclear phagocyte 2000; Yeung et al., 1998) (Figure 3). In the juxtamem- lineage has been demonstrated by studies with the brane (JM) domain of human CSF-1R, Tyr-561 is CSF-1 null mutant osteopetrotic (op/op) mouse autophosphorylated upon CSF-1 binding and associ- (Wiktor-Jedrzejczak et al., 1990). The op/op mouse ates with Src family of tyrosine kinases through their has impaired bone remodeling due to the absence of SH2 domain. In mouse CSF-1R, the homologous Tyr- osteoclasts, resulting in retarded skeletal growth and 559 site regulates phosphorylation and inactivation of excessive accumulation of bone in the ®rst 2 months of protein phosphatase 2A (PP2A), which is required for age, after which the defects gradually disappear. Other CSF-1-mediated dierentiation in M1 cells (McMahon populations of phagocytes are also depleted, including et al., 2001). The adaptor proteins Grb2 and Mona macrophages normally residing in liver, kidney, spleen interact with activated CSF-1R on Tyr-699, while Tyr- and gut, whereas lymph node macrophages are 723, another autophosphorylation site located within relatively intact. CSF-1 appears to act by providing the kinase insert (KI) domain of CSF-1R, interacts survival signals to mononuclear phagocytic cells, since with p85-PI3K and PLCg2. Src family kinases enforced expression of a bcl-2 transgene in monocytes participate in CSF-1-mediated activation of the PI3K/ of mice rescues macrophages and partially reverses Akt pathway (Grey et al., 2000; Lee and States, 2000), osteopetrosis (Lagasse and Weissman, 1997). In which is essential for CSF-1-induced cell survival. The addition, op/op mice display primary CNS neuronal suppressor of cytokine signaling (Socs1) associates de®cits, impaired fertility and increased apoptosis of directly with CSF-1R on Tyr-699 as well as Tyr-723 precursor B cells (Lu and Osmond, 2001; Michaelson (Bourette et al., 2001). The third autophosphorylation et al., 1996; Pollard et al., 1991). CSF-1R-de®cient site located in the KI is Tyr-708, which is required for mice show a more pronounced but similar osteope- Stat1 phosphorylation, although the kinase responsible trotic, reproductive, tissue macrophage and hemato- for Stat activation is presently unknown. Mutation of poietic phenotypes as op/op mice, including increased the major autophosphorylation site Tyr-809 in the splenic erythroid burst-forming units (BFU-E) and kinase domain of human CSF-1R severely impairs high-proliferative potential colony-forming cells (HPP- receptor-mediated mitogenesis in murine ®broblasts CFCs) (Dai et al., 2002) (Table 1). (Roussel et al., 1990). However, the equivalent mouse The v-fms gene of the Susan McDonough strain of Y807F mutant abrogates CSF-1-induced monocytic feline sarcoma virus (SM-FeSV) and feline c-fms dier dierentiation and conversely increases CSF-1-depen- only by nine scattered point mutations, both in dent proliferation (Bourette et al., 1995). Although no extracellular and intracellular domains, and by a C- direct interacting proteins at Tyr-809 have been terminal truncation in which 50 amino acids of c-fms are identi®ed, proteomic analysis reveals altered p45/52Shc replaced by 11 unrelated v-fms-coded residues (Wool- phosphorylation with the mouse Y807F CSF-1R ford et al., 1988). Mutational analysis has demonstrated mutant, while a non-phosphorylatable form of p45/ that the C-terminal domain of c-Fms possesses negative 52Shc prevents CSF-1-mediated macrophage dierentia- regulatory capability, whereas activating mutations in tion (Csar et al., 2001). codon 301 are required for complete transformation of Besides the molecules that associate directly with the murine ®broblasts. In mice, proviral integration of the activated CSF-1R, other proteins become also phos- Friend strain of murine leukemia virus (F-MuLV) phorylated, including multidomain docking protein upstream of the c-fms gene results in greatly increased Gab2 (Liu et al., 2001), inositol 5-phosphatase SHIP1 levels of c-fms transcription and CSF-1R expression, (Lioubin et al., 1996), Fms interacting protein FMIP which is associated with the onset of myeloid leukemia in (Tamura et al., 1999), tyrosine phosphatases Shp1 and the F-MuLV-infected mice (Gisselbrecht et al., 1987). In Shp2 (Carlberg and Rohrschneider, 1997; Yeung et al., human leukemias, c-FMS expression has been reported 1992), non-receptor protein kinase RAFTK (Related in a fraction of AML cases, mainly of the monocytic Adhesion Focal Tyrosine Kinase) (Hatch et al., 1998), lineage (Ashmun et al., 1989; Rambaldi et al., 1988). and Cbl (Wang et al., 1996). Cbl functions as a U3

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3324 ubiquitin ligase and CSF-1 stimulation induces Cbl- chemotaxis and adhesion of mast cells, as well as IgE- mediated CSF-1R multiubiquitination, which is fol- mediated degranulation (Vosseller et al., 1997). lowed by receptor internalization and degradation (Lee Recently, more information has become available on et al., 1999). Furthermore, induction of mitogenic interactions of signaling molecules with speci®c signaling after activation of the CSF-1R results in phosphorylated tyrosine residues located within the transcriptional upregulation of the cell cycle regulators human c-Kit receptor (Figure 3). The JM region of c- Cyclin D1, and Cyclin D2, and transcription factors c- Kit harboring Tyr-568 and Tyr-570 bind to the Src Myc and Ets-2, which is mediated through Src and the family members Lyn and Fyn (Linnekin et al., 1997; Raf/MEK/MAP kinase pathway (Aziz et al., 1999; Dey Price et al., 1997), Csk homologous kinase (CHK) and et al., 2000; Fowles et al., 1998). 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 c-Kit p62Dok1, which depends on PI3K activation (van Dijk et al., 2000). In the kinase insert (KI) domain, The c-KIT gene was identi®ed as the human counter- phosphorylated Tyr-703 interacts with the SH2 domain part of the HZ4 feline sarcoma virus harboring the v- of Grb2 (Thommes et al., 1999). The adaptor Kit gene, and found to be related to the receptor of the molecules Cbl, Gab1 and Gab2 become tyrosine- platelet-derived growth factor and CSF-1 (Yarden et phosphorylated and associate with Grb2 following al., 1987). Molecular cloning of the loci Dominant activation of c-Kit (Brizzi et al., 1996b; Nishida et white spotting (W) and Steel (Sl) present in natural al., 1999). In addition, Socs suppresses the mitogenic mouse mutants lead to the identi®cation of the mouse potential of c-Kit and associates with c-Kit probably c-Kit receptor and c-Kit ligand (KL) (Chabot et al., through binding to Grb2 (De Sepulveda et al., 1999). 1988; Huang et al., 1990). Loss-of-function mutations Mutational analysis has indicated that Tyr-721 in KI at either the W or Sl locus results in reduced thymic domain interacts with p85-PI3K (Serve et al., 1995). cellularity, depletion of erythroid precursors and mast PI3K inhibition abolishes Kit-mediated adhesion and cells, which is associated with macrocytic anemia cytoskeletal re-arrangement (Vosseller et al., 1997). KL (Table 1). In addition, there is hypopigmentation, stimulation induces phosphorylation of Crkl, which sterility and absence of interstitial cells of Cajal (ICC) associates with p85-PI3K and Cbl (Sattler et al., in the gut, resulting in reduced gut pacemaker activity. 1997b). PLCgl tyrosine phosphorylation is induced In humans, KIT mutations cause piebaldism, a after binding to Tyr-730 (Gommerman et al., 2000), syndrome resulting in deafness and abnormal skin and PLCg-stimulated Ca2+ in¯ux is critical for KL- and hair pigmentation (Fleischman et al., 1991; Giebel dependent cell survival (Gommerman and Berger, and Spritz, 1991). Within the hematopoietic lineage, c- 1998). In the C-terminus of c-Kit, autophosphorylation Kit is not only expressed on early hematopoietic stem site Tyr-936 interacts with both Grb2 and Grb7 cells, but also clonogenic myeloid, erythroid, mega- (Thommes et al., 1999). Deletion of the C-terminal karyocytic and dendritic progenitor cells, pro-B and domain alleviates Stat5 phosphorylation, but retains pro-T cells, and mature mast cells (Lyman and Stat1 activation, while absence of the KI domain Jacobsen, 1998). Two dierent isoforms of the murine completely abrogates Stat activation (Brizzi et al., and human c-Kit receptors exist in all of the cells 1999). Other substrates of c-Kit include Vav (Alai et examined, which dier in four amino acids (GNNK) al., 1992), and SHIP2 in association with Shc upstream of the transmembrane domain. Ligand- (Wisniewski et al., 1999). independent constitutive phosphorylation has been The biological signi®cance of several c-Kit-activated observed in the isoform missing these four amino acid signaling molecules has been addressed in speci®c gene residues (Reith et al., 1991). Furthermore, the GNNK- knock-out mouse studies. In the absence of the p85a isoform of c-Kit induces more prominent MAPK regulatory subunit of PI3K, KL-induced PI3K activa- phosphorylation and has a higher transforming tion, Akt phosphorylation and proliferation of mast capacity in NIH3T3 cells compared to the GNNK+ cells is partially inhibited (Lu-Kuo et al., 2000). isoform (Caruana et al., 1999). Cooperative action of PI3K and Src kinases is required KL is widely expressed during embryogenesis and to activate Rac and JNK/SAPK pathways and elicit c- can be detected on stromal cells, ®broblasts and Kit-mediated mast cell proliferation and suppression of endothelial cells. KL exists predominantly as a bivalent apoptosis induced by growth factor deprivation and g- dimer and can be expressed as membrane-associated or irradiation (Timokhina et al., 1998). Embryonic stem soluble form. KL supports the survival and self- cell-derived mast cells (ESMCs) de®cient for MAPK renewal of hematopoietic stem cells and therefore has activator MEKK2 display markedly reduced JNK/ been alternatively termed stem cell factor (SCF). KL SAPK kinase activation and cytokine production in synergizes with erythropoietin in stimulating erythroid response to KL stimulation (Garrington et al., 2000). progenitor cell proliferation and promotes megakar- This is not observed in MEKK1-nullizygous ESMCs, yocyte progenitor cell growth potential and maturation demonstrating clear speci®city for MEKK2 in signaling in combination with other cytokines, especially throm- c-Kit-mediated cytokine gene regulation. SHIP7/7 bopoietin (Lyman and Jacobsen, 1998). Furthermore, bone marrow-derived mast cells (BMMCs) show KL- KL is a potent enhancer of proliferation, survival, induced massive degranulation, which is not apparent

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3325 in SHIP+/+ BMMCs (Huber et al., 1998). This event TEL-PDGFRb (Golub et al., 1994). Other transloca- correlates with higher PtdIns(3,4,5)P3 (PIP3) levels in tion partners of PDGFRb in CMML are Huntingtin SHIP1-de®cient BMMCs. interacting protein 1 (HIP1) and Rabaptin5, corre- Several lines of evidence implicate c-Kit signaling in sponding to t(5;7)(q33;q11.2) and t(5;17)(q33;p13), hematological malignancies. Activating point muta- respectively (Magnusson et al., 2001; Ross et al., tions in c-Kit have predominantly been found in 1998). CMML has a clinical phenotype similar to patients with mastocytosis (Longley et al., 1996, 1999; CML, but is classi®ed as a MDS characterized by Nagata et al., 1995), a neoplastic disease involving dysplastic monocytosis, variable bone marrow ®brosis, mast cells. The most common mutation is found in the and progression to AML. Furthermore, H4(D10S170) phosphotransferase domain, substituting aspartic acid and CEV14 have been found as alternative fusion at codon 816 for valine at the same position (D816V). partners for the transmembrane and tyrosine kinase Activating D816V mutations have also been detected in domains of PDGFRb in atypical CML (aCML) and patients with myeloproliferative syndromes, AML acute monocytic leukemia in relapse (Abe et al., 1997; (Beghini et al., 2000; Ning et al., 2001a), and germ Kulkarni et al., 2000; Schwaller et al., 2001). The TEL cell tumors (Tian et al., 1999). Activation of PI3K and pointed (PNT) self-association motif, the HIP1 C- Stat3 contribute to transformation of hematopoietic terminal TALIN homology region, Rabaptin5 coiled- cells by Asp816 mutant of c-Kit (Chian et al., 2001; coil domains and both CEV14 and H4 leucine zipper Ning et al., 2001b). In addition, a number of in-frame domains promote ligand-independent PDGF b-recep- deletion or point mutations in the c-KIT juxtamem- tor dimerization and autophosphorylation, resulting in brane coding region have been identi®ed in mastocy- a constitutive active tyrosine kinase. It has been tomas as well as gastrointestinal stromal tumors demonstrated for most of the translocation-variants (GISTs). In a small subset of patients with MPD, that they confer factor-independent growth to Ba/F3 there are point mutations in the extracellular domain cells, while enforced expression of TEL-PDGFRb or of c-KIT, causing D52N substitution (Nakata et al., Rabaptin5-PDGFRb induces a myeloproliferative dis- 1995). Furthermore, 63% of AML patients show ease in a murine BMT model (Magnusson et al., 2001; increased c-Kit expression, while some cases exhibit Tomasson et al., 1999). Dysregulated myelopoiesis and deletion and insertion mutations in c-Kit extracellular predisposition for the development of myeloid or domain involving codon Asp-419 (Gari et al., 1999). lymphoid tumors is also evident in CD11a-TEL- Finally, a signi®cant fraction of sinonasal NK/T cell PDGFRb transgenic mice (Ritchie et al., 1999). lymphomas carry mutations in codon 825 (Hongyo et The PDGFRb is expressed on multipotent stem cell, al., 2000). Forthcoming studies still need to address the mast cell and myeloid cell lines in addition to implications of these newly identi®ed c-KIT mutations. myeloblastic leukemias (de Parseval et al., 1993; Foss et al., 2001). Cell populations within the hematopoietic organs known to express PDGF receptors include PDGFRb ®broblasts, early macrophage precursors, macrophages, smooth muscle cells and osteoblasts. T lymphocytes The platelet-derived growth factor receptors, PDGFRa and NK cells also express PDGFRb, and PDGF can and PDGFRb, are two highly related RTK, showing modulate the pattern of T cell cytokines produced in 85 and 75% identity between the two intracellular vitro and NK cell cytotoxicity (Daynes et al., 1991; kinase domains, but the kinase insert (KI) and the C- Gersuk et al., 1991). Under unsorted bone marrow terminal tail (CT) regions display only 27 and 28% culture conditions, PDGF is able to stimulate growth homology, respectively (Matsui et al., 1989). PDGF of primitive hematopoietic and erythroid precursors has mitogenic activity, primarily for mesenchymal cells, and promote megakaryocytopoiesis, most likely by but also promotes migration, dierentiation and matrix stimulating mesenchymal cells to cytokine production deposition. PDGF ligand consists of a family of (Delwiche et al., 1985; Yan et al., 1993; Yang et al., disulphide-bonded dimeric isoforms, PDGF-AA, 1995). Targeted disruption of the PDGFRb gene in PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. mice results in embryonic lethality just prior to birth, Mature PDGF-C and PDGF-D contain an N-terminal displaying hemorrhage, thrombocytopenia, anemia, region that must be proteolytically removed to enable dilated heart and defects in specialized smooth muscle receptor binding (Bergsten et al., 2001; LaRochelle et cells present in vascular capillaries in brain (pericytes) al., 2001; Li et al., 2000). PDGF-B and PDGF-D act as and kidney (mesangial cells) (Lindahl et al., 1998; agonistic ligands for PDGFRb, whereas PDGFRa Soriano, 1994) (Table 1). Studies in reconstituted binds all isoforms except PDGF-D. Interestingly, PDGFRb-de®cient chimeric mice argue that the PDGFR not only forms homo- and heterodimers hematopoietic defects arise secondary to possibly between the a- and b-subunit, but also dimerizes with metabolic stress and hypoxia, due to abnormal the epidermal growth factor receptor (EGFR) that can development of the placental labyrinth (Kaminski et be stimulated by PDGF (Saito et al., 2001). al., 2001). Interestingly, only the PDGFRb has been implicated At present, eleven autophosphorylation sites have in hematological malignancies, where a substantial been identi®ed in the cytoplasmic part of the PDGF fraction of chronic myelomonocytic leukemia (CMML) receptor-b (Figure 3). Two autophosphorylation sites shows t(5;12)(q33;p13), generating the fusion protein in the JM domain (Tyr-579 and Tyr-581) mediate the

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3326 binding of Src family tyrosine kinases (Mori et al., myeloid progenitor cells (Alimandi et al., 1997; Kubota 1993), the adaptor Shb (Karlsson et al., 1995), and et al., 1998). RasGAP suppresses cell migration tyrosine phosphorylation of Stat1, Stat3 and Stat5 directed through PDGF-signaling by silencing PLCgl (Sachsenmaier et al., 1999; Valgeirsdottir et al., 1998), activity (Valius et al., 1995). TEL-PDGFRb requires which involves a JAK-independent pathway (Vignais et engagement of PI3K and PLCgl to promote IL-3- al., 1996). Even though the Src pathway signals to independence in Ba/F3 cells (Sternberg et al., 2001), induce c-myc expression (Barone and Courtneidge, and induce lymphoid disease eciently in vivo 1995), activation of Src is apparently not required for (Tomasson et al., 2000). 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-PDGFRb- Concluding remarks induced myeloproliferative disease (Tomasson et al., 2000), and are necessary for full activation of Stat5 by Our increasing knowledge of the dierent signaling TEL-PDGFRb in Ba/F3 cells (Sternberg et al., 2001). components and the various pathways activated by Interestingly, mutating the two tryptophan residues 566 each of the oncogenic tyrosine kinases allows us to and 593, characteristic for the WW-like domain located obtain a better understanding of the range of biological in the JM region of H4-PDGFRb, severely compro- processes that are controlled by these kinases. In mises IL-3-independent survival of Ba/F3 cells addition, it provides a basis to design rational drugs (Schwaller et al., 2001). Furthermore, Val-536 muta- that may interfere with the tyrosine kinase activity, or tion within the JM domain of the wild type PDGFRb inhibit the action of critical signaling proteins that as well as similar mutations in PDGFRa, CSF-1R and mediate important biological activities of the activated c-Kit, result in constitutive activated tyrosine kinase oncogenic tyrosine kinases. activity (Irusta and DiMaio, 1998). These data There are many open questions in this ®eld. With the elaborate on a common ®nding that critical eector discovery of mutations in FLT3 it is now clear that at molecules important for oncogenic transformation least one third of AML patients carry activating alleles of interact with the JM domain of type III RTK. Flt3. Which other tyrosine kinases are activated in the The KI domain harbors six autophosphorylation remaining patients? This question applies equally well to sites. The SH2 and PH domain-containing molecules the other hematopoietic diseases, especially the broad Grb2 and Grb7 both interact with Tyr-716, while Grb7 collection of myeloproliferative disorders, like essential has also anity for phosphorylated Tyr-775 (Arvidsson thrombocythemia, agnogenic myeloid metaplasia and et al., 1994; Yokote et al., 1996). Two autophos- Polycythemia vera. Since more translocation break- phorylation sites Tyr-740 and Tyr-751 bind p85-PI3K points are being mapped to speci®c tyrosine kinases, (Kashishian et al., 1992). Tyr-751 serves also as a their signi®cance will also extend. Alternatively, it may docking site for the adaptor protein Ncka and may be worth looking for inactivating mutations in tyrosine compete with p85-PI3K for binding to the PDGFRb phosphatases, since at least in mice, inactivation of Shp1 (Nishimura et al., 1993). The autophosphorylation site or SHIP1 is associated with myeloproliferative disorders. Tyr-763 and Tyr-771 form binding sites for Shp2 and Another open question lies in the identi®cation of RasGAP, respectively (Kashishian et al., 1992; Ronn- signaling pathways by tyrosine kinase oncogenes that strand et al., 1999). In addition, Shp2 binds to Tyr- are either unique or shared, and required for transforma- 1009 in the C-terminal tail region, which serves as a tion. While it is now possible to generate kinase docking site for Nckb as well (Chen et al., 2000). inhibitors that are selective for each kinase, an PLCgl and adaptor protein APS, which is able to alternative strategy might be to target a common associate with Cbl, interact with Tyr-1021 (Yokouchi et pathway required for transformation by all kinases. al., 1999). The adaptor protein Shc may interact Overall, the frequent ®nding of genetic alterations in directly through multiple tyrosine residues or indirectly tyrosine kinase oncogenes in leukemias and lymphomas via association with other tyrosine-phosphorylated may be a cloud with a silver lining. Since there are proteins (Yokote et al., 1994). In addition, b1 good targets for drug development and inhibition of integrin-signaling results in tyrosine phosphorylation tyrosine kinase signaling generally leads to loss of cell of PDGFRb, which mediates FAK phosphorylation viability, many new drugs are likely to be identi®ed in and is dependent on Shp2 recruitment to Tyr-1002 (Qi the near future that have signi®cant clinical activity, et al., 1999; Sundberg and Rubin, 1996). with modest side eects. The tyrosine phosphorylation site residing in the catalytic domain (Tyr-857) is necessary for PDGF- mediated increase in kinase activity, but surprisingly Acknowledgments not enough for PDGF-dependent autophosphorylation B Scheijen provided the concept, design, collected the data, (Baxter et al., 1998). PLCgl and PI3K activation are drafted the paper and gave ®nal approval. JD Grin required for cell proliferation and migration of primary drafted the paper and gave ®nal approval. This work was ®broblasts and mesangial cells (Tallquist et al., 2000), supported by a fellowship of the Dutch Cancer Society and PDGFRb-mediated monocytic dierentiation in (KWF) to B Scheijen.

Oncogene Hematopoietic oncogenic tyrosine kinases B Scheijen and JD Griffin 3327 References

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