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 PDGFRbeta, 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.

Full text

Tyrosine kinase oncogenes in normal hematopoiesis and
hematological disease
Blanca Scheijen
1,2
and James D Grin*
,1,2
1
Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, MA 02115, USA;
2
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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
PDGFRb, that are normally involved in the regulation of
hematopoiesis or hematopoietic cell function. Despite
dierences 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 identi®ed in other kinases,
their immediate downstream targets, or in proteins
regulating their function.
Oncogene (200 2) 21, 3314 ± 3333. DOI: 10.1038/sj/
onc/1205317
Keywords: leukemia; lymphoma; protein tyrosine
kinase; signal transduction; translocation
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 identi®ed,
which largely can be classi®ed as receptor and non-
receptor tyrosine kinases (Blume-Jensen and Hunter,
2001). Receptor tyrosine kinases (RTKs) media te
cellular responses to a broad array of extracellular
signals involved in the regulation of cell proliferation,
migration, dierentiation and survival signaling. Li-
gand binding to the receptor initiates a cascade of
events, including receptor homodimerization, activa-
tion of intrinsic kinase activity, intermolecular tyrosine
trans-phosphorylation, association with signal-transdu-
cing proteins and phosphorylation of substrates (Weiss
and Schlessinger, 1998). Phosphorylat ed tyrosine
residues within speci®c sequence contexts serve as
high-anity docking sites for Src homology 2 (SH2)
domains-containing adaptor and eector 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 ®rst tyrosine kinase oncogene associated with
human hematologic disease, Bcr ± Abl, was identi®ed
almost twenty years ago, and there is now evidence for
involvement of multiple tyrosine kinase oncogenes in
acute and chronic leukemias, lymphomas, and myelo-
mas. 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 doma in to
adopt an activated con®guration. Activated tyrosine
kinase oncogenes generally cause enhanced prolifera-
tion and prolonged viability, but do not typically block
dierentiation. Common signaling pathways are in-
volved in mediating these eects, including activation
of phosphotidylinositol 3-kinases (PI3K), the Ras/Raf/
MAP kinases, phospholipase C-g (PLCg ), and Signal
transducers and activators of transcription (Stats). On
the other hand, tyrosine kinase oncogenes seem to be
associated with eithe r lymphoid or myeloid disorders.
It is not clear yet if some of the oncogenes have a
predilection for transforming one linea ge rather than
another, or if the lineage association is conferred by
the expression pattern of the translocation fusion
partner or modi®ed by cooperating oncogenes.
In this review, we will discuss a number of tyrosine
kinase oncogenes associated with hematopoietic neo-
plasia. Both unique and shared features will be
emphasized. Thei r role in normal hematopoiesis as
well as other relevant biological functions will be
considered, and signaling mechanisms descri bed in
more detail.
Abl kinase family
c-Abl/ARG
The mammalian Abl family of non-receptor tyros ine
kinases consists of c-Abl and ARG (Abl-related gene),
which share 89, 90 and 93% identi ty in their Src
homology region (SH) 3, SH2 and tyrosine kinase
Oncogene (2002) 21, 3314 ± 3333
ã
2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00
www.nature.com/onc
*Correspondence: JD Grin;
E-mail: james_grin@dfci.harvard.edu

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 ®lamentous (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 varia nt protein products denoted
as type Ia and Ib. The type Ib variant contains a
consensus sequence for N-terminal myristylation. The
c-Abl proto-onco gene was originally identi®ed as the
cellular counterpart of v-Abl, encoded by the Abelson
murine leukemia virus. Subsequently, it was demon-
strated that c-Abl is involved in two dierent
chromosomal translocations present in human leuke-
mias, 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, TEL ± ARG fusion transcripts have been
identi®ed 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 suscept-
ibility 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 de®cient 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
7/7
/arg
7/7
neuroepithelial cells show
gross alterations in their actin cytoskeleton. Direct
interaction of Abl family kinases wi th G- and F-actin
(Van Etten et al ., 1994), as well as cytoskeletal-
associated proteins Hef1 (Law et al., 1996), amphiphy-
sin-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
signi®cance to coordinate cytoske letal functions. Inter-
estingly, recent data show that c-abl
7/7
/arg
7/7
®broblasts display increased motility, and argue that
both c-Abl and Arg negatively regulate cell migration
by disrupting Crk-p130
CAS
complex formation (Kain
and Klemke, 2001).
Several lines of evidence suggest a positive role of
c-Abl in cell cycle regulation. In quiescent and G
1
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 dom ain
of c-Abl thereby inhibiting its kinase activity. Phos-
phorylation of pRB by cycli n D-Cdk4/6 disrupts the
c-Abl/pRB complex at the G
1
/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
Table 1 Overview in vivo phenotypes of tyrosine kinase gene-de®cient mice
Tyrosine kinase gene(s) Hematological defects Non-hematological phenotypes
abl
7/7
Hypocellular thymus and spleen, lymphopenia, susceptibility Early postnatal lethality, runted defective craniofacial
to bacterial infections, reduced pro-B cells in BM and eye development
arg
7/7
None Runted at age of 3 weeks
Reduced motor skills and mating behavior,
abnormal reflexes
arg
7/7
abl
7/7
Not determined Lethal E10.5, defective neurulation, enhanced
amount of apoptotic cells in all tissues
c-fes
7/7
Reduced B cell numbers and more myeloid cells, None
compromised innate immunity, diminished
adhesion ability of macrophages
flt3
7/7
Less precursor B cells in BM, reduced reconstitution None
capacity of the lymphoid lineage
csf1r
7/7
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-kit
7/7
(W/W) Depletion erythroid precursors and mast Hypopigmentation, sterility, absence of
cells, reduced thymic cellularity ICC cells in gut
PDGFRb
7/7
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
3315

contribute to the phosphorylation of the C-terminal
domain (CTD) of RNA polymerase II, possibly
promoting transcription elongat ion (Baskaran et al.,
1993; Duyster et al., 1995). Conversely, c-Abl abro-
gates pRB-mediated growth arrest in SAOS-2 cells,
which are de®cient 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-Robert s et al., 1995,
1997). Fibroblasts de®cient of c-Abl displayed delayed
entry into S-phase upon PDGF stimulation (Plattner et
al., 1999), while c-abl
7/7
B lymphocytes show reduced
mitogenic response to interleukin (IL)-7 and LPS
(Hardin et al., 1996). Furthermore, c-Abl contributes
to enhanced pro liferation of p53-de®cient cells (Whang
et al., 2000).
On the other hand, overexpression of c-Abl results in
aG
1
-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 eects relate to the ability of c-A bl to induce a
G
1
-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; Sha fman et al.,
1997). Subsequently, c-Abl interacts with p53 and
enhances p53-mediated transcript ion and growth sup-
pression (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 eectors activated after
genotoxic stress, since targeted gene-inactivation experi-
ments 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 de®cient
in c-Abl fail to activate JNK/SAPK and p38 MAPK
after treatment with certain DNA-damaging agents
(Kharbanda et al., 1995; Pande y et al., 1996), which
correlates with the ability of c-Abl to bind and
stimulate the activity of the upstream eectors 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 regula tes 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 d (PKCd) (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 p210
Bcr ± Abl
. The p185
Bcr ± Abl
is characteristic for Ph
+
acute lymphocytic leukemia (ALL) , whi le p230
Bcr ± Abl
has been detected in chronic neutrophilic leukemia. All
Bcr ± Abl variants contain elevated tyrosine kinase
activity co mpared to c-Abl, but among the three forms,
p185
Bcr ± Abl
shows the strongest activity. Whereas each
Bcr ± Abl protein harbors the coiled-coil (CC) oligomer-
ization domain (amino acids 1 ± 63) and the serine/
threonine kinase domain (amino acids 64 ± 414) in the
Bcr region, the Dbl/CDC24 g uanine nucleotide ex-
change factor (GEF) homology (Dbl) domain and
pleckstrin homology (PH) domain (amino acids 734 ±
866) are absent in p185
Bcr ± Abl
. The CC oligomerizatio n
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 ecient oncogenic transformation
by p210
Bcr ± 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
®broblasts, but is evident in hematopoietic cells and
requires the presence of a functi onal 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-kB, 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 be tween 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
Grin, 2000; Sillaber et al., 2000). However, myeloid
cells de®cient in Stat5a/b display unaltered transforma-
tion eciency by p210
Bcr ± Abl
(Sexl et al., 2000).
Bcr ± Abl inhibits apoptosis in cells exposed to DNA
damage, cytokine deprivation and Fas activation,
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3316
Oncogene

which involves several mechanisms blocking mito chon-
drial release of cytochrome c and procaspase-3
activation (Amarante-Mendes et al., 1998b; Dubrez et
al., 1998). These include Bad phosphorylat ion (Neshat
et al., 2000), and induction of Bcl2 and Bcl-x
L
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 p27
Kip1
levels may
contribute to enhanced survival signaling in hemato-
poietic cells (Gesbert et al., 2000; Jonuleit et al., 2000;
Parada et al., 2001).
Besides its established role in preventing pro-
grammed cell death, the eects of Bcr ± Abl on
hematopoietic cell dierentiation are less well de®ned.
Bcr ± Abl increases the myeloid cell compartment after
retroviral transduction of murine bone marrow, but
does not alter the fundamental potential of HSC to
dierentiate 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
dierentiation of the myeloid precursor cell line 32D,
by inducing the expression of the RNA-bi nding protein
hnRNP-E2, thereby suppressing C/EBPa translation
and consequently transcriptional activation of granu-
locyte 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 transforma-
tion (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 su bunit 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 high ly phosphorylated protein
p62
Dok1
(Carpino et al., 1997; Yamanashi and
Baltimore, 1997), or its homolog p56
Dok2
(Di Cristofa-
no et al., 1998), and tyrosine phosphorylation of
p62
Dok1
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 eector 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 identi®ed as one of the major tyrosine phosphory-
lated 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 p130
CAS
(Salgia et al., 1996a), Hef1/C as-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 Nckb
(Coutinho et al., 2000) are additional adaptor proteins
that associate with Bcr ± Abl, while PLCgl (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 express ing Bcr ± Abl.
It has been a dicult challenge to recapitulate the
p210
Bcr ± Abl
-induced chronic myeloid disease in a mouse
model (Wo ng 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-p210
Bcr ± 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 an d 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., 200 1; 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 ons et 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
Oncogene
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3317

restricted to speci®c 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/nu cleophosmin (NPM)
(Morris et al., 1994; Shiota et al., 1994), a ubiquitously
expressed RNA-binding nucleolar phosphoprotein cap-
able of shuttling newly synthesized proteins between
nucleolus and cytoplasm (Bor er et al., 1989). The
chimeric gene NPM ± ALK is produced by the chromo-
somal 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 homodim ers, resulting in the constitutive activa-
tion of the catalytic ALK tyros ine kinase domain
(Bischof et al., 1997; Fujimoto et al., 1996).
NPM ± ALK is capable of transforming rodent
®broblasts (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 cyto-
plasmic 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 transform ation by NPM ± ALK, nuclear
localization, which occurs through heterodimer ization
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
PLCgl 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 PLCg-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
identi®ed alternative fusion partner s of the ALK
cytoplasmic domain in ALCL (Figure 2). These include
the nonmuscle tropom yosins TPM3 and TPM4 at
t(1;2)(q21;p23) and t(2;19)(p23;p13.1) respectively (La-
mant et al., 1999; Meech et al., 2001; Siebert et al.,
1999), two dierent variants of TFG (tropomyosin
receptor kinase-fused gene) at t(2;3)(p23;q21) (Hernan-
Figure 1 Schematic diagram showing the various structural motifs within p210
Bcr-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
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3318
Oncogene

dez 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 ®ndings that the oncogenic
potential of ALK is not dependent on its nuclear
localization. However, similar to NPM, all other
variant fusion proteins contain speci®c multimerization
regions, and each of them is capable of eliciting ALK
tyrosine kinase activation.
Besides its prominent role in CD30
+
ALCL, there is
considerable amount of data to suggest that constitu-
tive activation of the ALK kinase is also involved in
the pathogenesis of an unrelated disease, called
in¯ammatory myo®broblastic tumors (IMT) (Con et
al., 2001; Grin et al., 1999). IMTs consist of spindle
shaped myo®broblasts with a pseudosarcomatous
in¯ammatory appearance and arise mostly in the
abdomen of children and adolescents (Con 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 identi®cation of clonal
chromsomal aberrations involving TPM3 ± ALK,
TPM4 ± ALK, CLTC ± ALK and RanBP2 ± ALK 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 speci®c oncogene tyrosine kinase, but is able to
transform dierent mesenchymal cell types.
c-Fes/Fps
The c-Fes/Fps proto-oncogene is the mammalian
equivalent of the v-fes transforming oncogene asso-
ciated 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
(Groen 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),
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 dierent TFG variants, generating two distinct fusion
proteins. The asterisk indicates that the reported translocation involving RanBP2 has not yet been cytogenetically con®rmed
Oncogene
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3319

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 modi®ed by N-terminal myristylation. All
three structural domains of p95
c-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, provid-
ing 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 ®rst CC domain
activates Fes tyrosine activity, which is signi®cantly
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 pro-
genitor 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 (Feld-
man et al., 1983; Yates et al., 1995), although more
recent data demonstrate p93
c-Fes
protein localization
within the Golgi network and cytoplasmic vesicles,
arguing for a role of Fes in vesic ular tracking
(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 form s 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 (Matsu-
da et al ., 1995). Fes interacts also with the IL-4Ra
subunit and becomes tyrosine phosph orylated by JAK1
upon ligand binding (Izuhara et al., 1994; Jiang et al.,
2001). The involvement of Fes in mediating signals
downstream of the common b (b
c
) 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 b
c
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
con®rmed 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).
Identi®ed substr ates 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 Smith-
gall, 1996), but induces association with Grb2/mSOS,
the Ras guanine nucleotide exchange factor complex
(Maru et al., 1995). Signaling downstream of the IL-
4Ra involves Fes-mediated PI3K recruitment and
activation of p70
S6K
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 ®broblast 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 dierentiation 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 p93
c-Fes
protein is especially high in
acute and chronic myeloid leukemias (Smithgall et al.,
1991), although this may merely re¯ect the myeloid
component of these malignancies. An aberrant trun-
cated c-Fes transcript is expressed in various lympho-
ma 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-)®brosarcomas,
hemangiomas and angiosarcomas in transgenic mice
(Yee et al., 1989), whereas mice transgenic for
myristylated c-Fes develop multifocal hemangiomas,
but display no suscept ibility 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 dier-
entiation (Smithgall et al., 1988; Yu and Glazer, 1987).
In fact, c-Fes overexpression restores the capability of
K562 leukemic cells to unde rgo myeloid dierentiation
(Yu et al., 1989). Inhibition of Fes protein levels by
antisense oligodeoxynucleotides in HL60 prevent s
granulocytic and macrophage dierentiation (Ferrari
et al., 1994; Manfredini et al., 1993, 1997). Ho wever,
studies in c-fes
7/7
mice show that Fes is dispensable
for normal development of the myeloid lineage. The
only functional defect in Fes-de®cient mice relates to
the decreased adhesion capacity of c- fes
7/7
macro-
phages, 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
7/7
macrophages.
No dierences are observed with IL-3 and IL-10, and
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3320
Oncogene

c-fes
7/7
neutrophils display normal patterns of activa-
tion. 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 recept ors (fetal liver kinase 2) (Mat-
thews et al., 1991). The human homologue, alterna-
tively 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 (PDGFRa and PDGFRb). Each
of these receptor molecules has ®ve 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 pr otein, 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 nondisul®d e-linked homo-
dimeric glycopr otein 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 tw o monomers forming an antiparallel dimer
(Savvides et al., 2000). FL mRNA transcripts are
present in a wide variety of human an d 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 CD4
7
CD8
7
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; Meierho 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 dierentially 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, mega-
karyocyte, eosinophil, or mast cell lineages (Hirayama
et al., 1995; Hudak et al., 1995; Jacobsen et al., 1995).
No restrictions in species speci®city has been observed
for the eects 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 seven-
fold, respectivel y (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
7
subsets (Maras-
kovsky et al., 2000; Pulendran et al., 2000). Since DC
are the most ecient 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
PLCg (Dosil et al., 1993; Marchetto et al., 1999;
Rottapel et al., 1994). Although no speci®c Tyr
residues have been mapped which mediate the
interaction with speci®c 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 (Lav agna-
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 signi®cance of
Stat5a in Flt3 signaling is illustrated by the fact that
only Stat5a
7/7
, and not Stat5b
7/7
, bone marrow
progenitor cells are unresponsive to FL-mediated
proliferative eects (Zhang et al., 2000).
Detailed analysis in ¯t3
7/7
mice has indicated that
mainly primitive B lymphoid progenitor cells are
aected in the absence of Flt3 expression (Mackar-
Oncogene
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3321

ehtschian 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 indis-
tinguishable between ¯t3
7/7
and wild-type mice.
Although the Flt3 receptor is expressed on murine
and human cell populations enriched for hematopoietic
stem and progenitor cells, the populati on of multi-
potential and myeloid colony- forming progenitors is
not aected in ¯t3
7/7
mice. Only competitive
repopulation experiments reveal a signi®cant defect of
Flt3-de®cient stem cells, where reconstitution of the
hematopoietic system is less ecient in comparison to
wild-type stem cells, especially of the lymphoid lineage.
In contrast, ¯t3L
7/7
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 signi®cant reduction, similar to
¯t3 receptor-de®cient mice. In addition, ¯t3L
7/7
mice
have decreased numbers of myeloid-related
(CD8a
7
CD11c
hi
) and lymphoid-related (CD8a
+
CD11-
c
hi
) DC and are de®cient in NK cells. At present it is
unclear whether these distinct phenotypes re¯ect true
dierences between ¯t3
7/7
and ¯t3L
7/7
mice or relates
to mice strain variations.
One important indication implicating Flt3-mediated
signaling in the pathogenesis of myeloid leukemia has
been the identi®cation of an internal tandem duplica-
tion (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-NE
Y-
F
YVDFREYEYD-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). Rem arkably, elongation of the JM
portion rather than introduction of new tyrosine
residues generates ligand-independent dimerized ver-
sions 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 activa-
tion 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 (Yama-
moto et al., 2001), arguing that each variant may
contribute to the pathogenesis of acute leukemia.
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
eector 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)
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3322
Oncogene

c-Fms/CSF-1R
The c-fms proto-oncogene encodes for the receptor of
colony-stimulating factor-1 (CSF-1), also called macro-
phage colony-stimula ting factor (M-CSF), which is a
lineage-speci®c cytokine stimulating proliferation and
dierentiation of monocyte progenitors and supporting
the survival of mature macrophages (Stanley et al.,
1983). The CSF-1 R 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,
cm
+
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 demonst rated 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 ®rst 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 CN S neuronal
de®cits, impaired fertility and increased apoptosis of
precursor B cells (Lu and Osmond, 2001; Michaelson
et al., 1996; Pollard et al., 1991). CSF-1R-de®cient
mice show a more pronounced but similar osteope-
trotic, reproductive, tissue macrophage and hemato-
poietic 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 dier
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 (Wool-
ford 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 ®broblasts. 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 juxtamem-
brane (JM) domain of human CSF-1R, Tyr-561 is
autophosphorylated upon CSF-1 binding and associ-
ates 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 dierentiation in M1 cells (McMahon
et al., 2001). The adaptor pro teins Grb2 and Mon a
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 PLCg2. 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 ®broblasts
(Roussel et al., 1990). However, the equivalent mouse
Y807F mutant abrogates CSF-1-induced monocytic
dierentiation and conversely increases CSF-1-depen-
dent proliferation (Bourette et al., 1995). Although no
direct interacting proteins at Tyr-809 have been
identi®ed, proteomic analysis reveals altered p45/52
Shc
phosphorylation with the mouse Y807F CSF-1R
mutant, while a non-phosphorylatable form of p45/
52
Shc
prevents CSF-1-mediated macrophage dierentia-
tion (Csar et al., 2001).
Besides the molec ules that associate directly with the
activated CSF-1R, other proteins become also phos-
phorylated, 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
Oncogene
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3323

ubiquitin ligase and CSF-1 stimulation induces Cbl-
mediated CSF-1R multiubiquitination, which is fol-
lowed 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 identi®ed as the human counter-
part 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 identi®cation 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, mega-
karyocytic and dendritic progenitor cells, pro-B and
pro-T cells, and mature mast cells (Lyman and
Jacobsen, 1998). Two dierent isoforms of the muri ne
and human c-Kit receptors exist in all of the cells
examined, which dier in four amino acids (GNNK)
upstream of the transmembrane domain. Ligand-
independent constitutive phosphorylation has bee n
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, ®broblasts 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 term ed stem cell factor (SCF). KL
synergizes with erythropoietin in stimulating erythroid
progenitor cell proliferation and promotes megakar-
yocyte progenitor cell growth potential and maturation
in combination with other cytokines, especially throm-
bopoietin (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 speci®c
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
p62
Dok1
, 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 phosp horylation of Crkl, which
associates with p85-PI3K and Cbl (Sattler et al.,
1997b). PLCgl tyrosine phosphorylation is induced
after binding to Tyr-730 (Gommerman et al., 2000),
and PLCg-stimulated Ca
2+
in¯ux 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 signi®cance of several c-Kit-activated
signaling molecules has been addressed in speci®c gene
knock-out mouse studies. In the absence of the p85a
regulatory subunit of PI3K, KL-induced PI3K activa-
tion, 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 g-
irradiation (Timokhina et al., 1998). Embryonic stem
cell-derived mast cells (ESMCs) de®cient 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 speci®city for MEKK2 in signaling
c-Kit-mediated cytokine gene regulation. SHIP
7/7
bone marrow-derived mast cells (BMMCs) show KL-
induced massive degranulation, which is not apparent
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3324
Oncogene

in SHIP
+/+
BMMCs (Huber et al., 1998). This event
correlates with higher PtdIns(3,4,5)P3 (PIP
3
) levels in
SHIP1-de®cient BMMCs.
Several lines of evidence implicate c-Kit signaling in
hematological malignancies. Activating point muta-
tions in c-Kit have predominantly been found in
patients with mastocytos is (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 myel oproliferative 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 Asp
816
mutant of c-Kit (Chian et al., 2001;
Ning et al., 2001b). In addition, a num ber of in-frame
deletion or point mutations in the c-KIT juxtamem-
brane coding region have been identi®ed in mastocy-
tomas 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 inser tion mutations in c-Kit extracellular
domain involving codon Asp-419 (Gari et al., 1999).
Finally, a signi®cant 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 identi®ed c-KIT mutations.
PDGFRb
The platelet-derived growth factor receptors, PDGFRa
and PDGFRb, 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, dierentiation 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 PDGFRb, whereas PDGFRa
binds all isoforms except PDGF-D. Interestingly,
PDGFR not only forms homo- and heterodimers
between the a- and b-subunit, but also dimerizes with
the epidermal growth factor receptor (EGFR) that can
be stimulated by PDGF (Saito et al., 2001).
Interestingly, only the PDGFRb 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-PDGFRb (Golub et al., 1994). Other transloca-
tion partners of PDGFRb in CMML are Huntingtin
interacting protein 1 (HIP1) and Rabaptin5, corre-
sponding 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 classi®ed as a MDS characterized by
dysplastic monocytosis, variable bone marrow ®brosis,
and progression to AML. Furthermore, H4(D10S170)
and CEV14 have been found as alternative fusion
partners for the transmembrane and tyrosine kinase
domains of PDGFRb 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 b-recep-
tor 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-PDGFRb or
Rabaptin5-PDGFRb induces a myeloproliferative dis-
ease 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-
PDGFRb transgenic mice (Ritchie et al., 1999).
The PDGFRb 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
®broblasts, early macrophage precursors, macrophag es,
smooth muscle cells and osteoblasts. T lymphocy tes
and NK cells also express PDGFRb, 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 PDGFRb 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
PDGFRb-de®cient chimeric mice argue that the
hematopoietic defects arise secondary to possibly
metabolic stress an d hypoxia, due to abnormal
development of the placental labyrinth (Kaminski et
al., 2001).
At present, eleven autophospho rylation sites have
been identi®ed in the cytoplasmic part of the PDGF
receptor-b (Figure 3). Two autophosphorylation sites
in the JM domain (Tyr-579 and Tyr-581) mediate the
Oncogene
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3325

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 G
0
/G
1
transi-
tion. In contrast, Tyr-579 and Tyr-581 appear to be
critical for the development of the TEL-PDGFRb-
induced myeloproliferative disease (Tom asson et al.,
2000), and are necessary for full activation of Stat5 by
TEL-PDGFRb 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-PDGFRb, severely compro-
mises IL-3-independent survival of Ba/F3 cells
(Schwaller et al., 2001). Furthermore, Val-536 muta-
tion within the JM domain of the wild type PDGFRb
as well as similar mutations in PDGFRa, CSF-1R and
c-Kit, result in constitutive activated tyrosine kinase
activity (Irusta and DiMaio, 1998). These data
elaborate on a common ®nding that critical eector
molecules impor tant 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 anity for phosphorylated Tyr-775 (Arvidsson
et al., 1994; Yokote et al., 1996). Two autophos-
phorylation sit es Tyr-740 and Tyr-751 bind p85-PI3K
(Kashishian et al., 1992). Tyr-751 serves also as a
docking site for the adaptor protein Ncka and may
compete with p85-PI3K for binding to the PDGFRb
(Nishimura et al., 1993). The autophosphorylation site
Tyr-763 and Tyr-771 form binding sites for Shp2 and
RasGAP, respectively (Kashishian et al., 1992; Ronn-
strand et al., 1999). In addition, Shp2 binds to Tyr-
1009 in the C-terminal tail region, which serves as a
docking site for Nck b as well (Chen et al., 2000).
PLCgl 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, b1
integrin-signaling results in tyrosine phosphorylation
of PDGFRb, 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 kin ase activity, but surprisingly
not enough for PDGF-dependent autophosphorylation
(Baxter et al., 1998). PLCgl and PI3K activation are
required for cell proliferation and migration of primary
®broblasts and mesangial cells (Tallquist et al., 2000),
and PDGFRb-mediated monocytic dierentiation in
myeloid progenitor cells (Alimandi et al., 1997; Kubota
et al., 1998). RasGAP suppresses cell migration
directed through PDGF-signaling by silencing PLCgl
activity (Valius et al., 1995). TEL-PDGFRb requires
engagement of PI3K and PLCgl to promote IL-3-
independence in Ba/F3 cells (Sternberg et al., 2001),
and induce lymphoid disease eciently in vivo
(Tomasson et al., 2000).
Concluding remarks
Our increasing knowledge of the dierent signal ing
components and the various pathways acti vated 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 ®eld. 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 break-
points are be ing mapped to speci®c tyrosine kinases,
their signi®cance 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 identi®cation of
signaling pathways by tyrosine kinase oncogenes that
are either unique or shared, and required for transforma-
tion. W hile 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 ®nding 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 identi®ed in
the near future that have signi®cant clinical activity,
with modest side eects.
Acknowledgments
B Scheijen provided the concept, design, collected the data,
drafted the paper and gave ®nal approval. JD Grin
drafted the paper and gave ®nal approval. This work was
supported b y a fellowship of the Dutch Cancer Society
(KWF) to B Scheijen.
Hematopoietic oncogenic tyrosine kinases
B Scheijen and JD Griffin
3326
Oncogene

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