Tyrosine Kinase Oncogenes in Normal Hematopoiesis and Hematological Disease
Total Page：16
File Type：pdf, Size：1020Kb
Oncogene (2002) 21, 3314 ± 3333 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc 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 in- volved 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-transdu- cing 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: [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