Vol. 9, 535–550, February 2003
Clinical Cancer Research 535
Minireview
Modulation of Cellular Signaling Pathways: Prospects for Targeted
Therapy in Hematological Malignancies
Farhad Ravandi,1 Moshe Talpaz, and Zeev Estrov
Department of Hematology/Oncology, The University of Illinois at
Chicago, Chicago, Illinois 60612 [F. R.], and Department of
Bioimmunotherapy, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030 [M. T., Z. E.]
Abstract
The high remission rates observed in patients with
chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in
cellular biology over the past decade has resulted in a better
understanding of the process of malignant transformation, a
better classification of subtypes of each disease on the basis
of molecular markers, and a better characterization of the
molecular targets for drug development. These advances
have already spawned the development of such effective
agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in
hematological malignancies.
Introduction
Cellular proliferation, differentiation, and death are regulated by a number of extracellular molecules such as cytokines
and hormones, as well as intercellular interactions mediated by
neighboring cell surface antigens. These effectors mediate gene
transcription either directly or indirectly by activating intracellular signaling pathways, which in turn activate appropriate
cellular machinery (1). Cell-surface receptors that convert external stimuli into intracellular signals are pivotal in this signaling process. They activate intracellular pathways either through
their inherent enzymatic function or as a result of their association with other catalytic proteins. Indeed, most growth factors
and cytokines bind these receptors and exert their function
through their activation, commonly by phosphorylation (1).
Normal hematopoiesis is dependent on intricately regulated
signaling cascades that are mediated by cytokines and their
receptors. Orderly function of these pathways leads to the generation of appropriate constellation of hematopoietic cells, and
their abnormal activation results in neoplastic transformation,
impaired apoptosis, and uncontrolled proliferation. Cytokines
Received 6/25/02; revised 9/5/02; accepted 9/6/02.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
1
To whom requests for reprints should be addressed, at University of
Illinois—Chicago, 840 South Wood Street, MC 787 Chicago, IL 606127323. Phone: (312) 996-5982; Fax: (312) 413-4131; E-mail: ravandi@
uic.edu.
function in a redundant and pleiotropic manner; different cytokines can exert similar effects on the same cell type, and any
particular cytokine can have several differing biological functions (2). This complexity of function is a result of shared
receptor subunits as well as overlapping downstream pathways
culminating in activation of common transcription factors (3).
The signal transduction cascades involve three major
classes of proteins: kinases, adaptor or docking proteins, and
transcription factors. Early insights into the cellular signaling
pathways came from studies of IFN function (4 – 6). These
experiments led to the identification of a family of nonreceptor
TKs2 called Jaks and their target proteins, Stats, which mediate
gene transcription (4, 7). The Jak-Stat pathways are commonly
activated during cytokine signaling through phosphorylation of
specific tyrosine residues (3). The interaction of a cytokine with
its receptor induces its tyrosine phosphorylation and leads to
activation of downstream protein TKs including Jaks and Stats.
Apart from their catalytic domain, protein TKs contain several
other characteristic motifs including the SH2, SH3, and pleckstrin homology domain, which enable them to interact with
other signaling molecules and propagate the message (8, 9).
The phosphorylation of serine and threonine residues is
integral to the activation of numerous other intracellular proteins
that mediate a number of other signaling pathways (10). Cytokine receptors without intrinsic kinase activity transmit their
signals primarily through activation of Jak kinases. These receptors as well as those with intrinsic kinase activity, the RTKs,
were previously thought to transmit their signals independently
of the serine/threonine kinase cascades. More recently, it has
been established that both of these pathways interact with serine/threonine kinase cascades such as the Ras/Raf/MEK/ERK
(MAPK; Ref. 10). For example, after ligand binding, the ␤subunit of IL-3 and GM-CSF receptors are phosphorylated and,
through recruitment of adaptor proteins such as Shc, Grb2, and
2
The abbreviations used are: TK, tyrosine kinase; Jak, janus kinase;
Stat, signal transducer and activator of transcription; ERK, extracellular
signal-regulated kinase; MAPK, mitogen-activated protein kinase; IL,
interleukin; GM-CSF, granulocyte macrophage colony-stimulating factor; JNK, c-Jun NH2-terminal kinase; SAPK, stress-activated protein
kinase; PKB, protein kinase B; PI3K, phosphatidylinositol 3⬘-kinase;
PDGFR, platelet-derived growth factor receptor; TNF, tumor necrosis
factor; SHP-1, SH-2 domain containing protein tyrosine phosphatase-1;
SOCS, suppressor of cytokine signaling; PIAS, protein inhibitor of
activated stat; RTK, receptor tyrosine kinase; FLT3R, FMS-like tyrosine
kinase 3 receptor; Grb2, growth factor receptor binding protein 2; RSK,
ribosomal S6 kinase; AML, acute myeloid leukemia; CML, chronic
myelogenous leukemia; ALL, acute lymphoblastic leukemia; MEK,
mitogen-activated protein/extracellular signal-regulated kinase kinase;
ALK, anaplastic lymphoma kinase; NPM, nucleophosmin; ATRA, alltrans-retinoic acid; APL, acute promyelocytic leukemia; NF␬B, nuclear
factor ␬B; I␬B, inhibitor of nuclear factor-␬B; HDAC, histone deacetylase; IAP, inhibitor of apoptotic pathway; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; Rb, retinoblastoma;
RAR, retinoic acid receptor; XIAP, X-linked inhibitor of apoptosis.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
536 Cellular Signaling Pathways as Therapeutic Targets
Sos, activate the Ras signaling pathway (11). This in turn
activates Raf followed by downstream activation of ERK1 and
ERK2, and increased expression of transcription factors c-fos
and c-jun (12–14). Other members of the MAPK family such as
p38, and JNK/SAPK are also activated after phosphorylation of
their serine/threonine residues as a result of cytokine/receptor
interaction (15–18). Similarly, PI3K associates with the ␤ chain
of IL-3 receptor, recruits PKB/AKT by phosphorylation of its
serine residues, and transmits cellular survival signals (19 –21).
Another downstream protein to IL-3 activation is the p70S6
kinase, which also interacts with the ␤ chain and mediates
appropriates signals (22, 23). Ultimately, these pathways influence gene transcription through their ability to recruit transcription factors, regulate apoptosis through the phosphorylation of
apoptotic proteins, and cause the cell to progress through cellcycle checkpoints by activation of specific kinases.
Of considerable interest is the description of a number of
oncogenes with constitutive kinase activity. These molecules are
derived from genes including c-ABL, c-FMS, FLT3, c-KIT, and
PDGFR␤, which are normally involved in the regulation of
hematopoiesis (24). The kinase activity of the oncogene is
constitutively activated by mutations that remove inhibitory
domains of the molecule or induce the kinase domain to adopt
an activated configuration (24). As a result of such constitutive
activation a number of signaling cascades such as the Jak-Stat
pathway, the Ras/Raf/MAPK pathway, and the PI3K pathway
are activated.
With better characterization of aberrant signaling through
the cell surface receptors and their downstream pathways in
neoplastic cells, current research is exploring ways to reverse
such dysregulated stimuli (25). Here, we will briefly review the
role of cellular signaling pathways in normal cellular processes,
neoplastic transformation, and development of hematological
malignancies. We then explore the possible ways that their
modulation can lead to clinically meaningful benefits.
Jak-Stat Signaling Pathways
Hematopoietic cell proliferation and differentiation is regulated by a number of soluble polypeptides such as IFNs,
interleukins, and colony-stimulatory factors known collectively
as cytokines (26). Cytokines bind to their cognate receptors and
mediate downstream effects. A cytokine receptor consists of a
unique ligand binding subunit as well as a signal transducing
subunit, which may be structurally similar to the other cytokine
receptors (27–29). On the basis of their characteristic structural
motifs in their extracellular domains a number of subfamilies of
cytokine receptors have been identified (27, 29, 30). These
include the gp130 family, the IL-2 receptor family, the growth
hormone receptor family, the IFN family, and the gp140 family
of receptors (3). A detailed description of the structure of these
receptors is beyond the scope of this review, but in general they
consist of two or more subunits including the ␣, ␤, and ␥ chains
(3, 27). For example, the IL-2 receptor family includes the
receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 each consisting of
a ligand-binding ␣-subunit, and signal transducing ␤ and ␥
subunits. Alternatively, the gp140 family including the receptors
for IL-3, IL-5, and GM-CSF have a unique ligand-binding
␣-subunit and a common ␤ (gp140) signal-transducing unit (3).
Fig. 1 The Jak-Stat pathway and its regulation.
Unlike growth factor receptors (RTKs), cytokine receptors
do not possess a cytoplasmic kinase domain, and most cytokines
transmit their signal by recruiting other TKs (3). Dimerization of
the cytoplasmic component of the cytokine receptor as a result
of ligand binding is the initial step in the initiation of cellular
signaling (31). The dimerized subunits then associate with intracellular TKs such as members of the Src or Jak families of
kinases, and the signal is propagated (Fig. 1). Different Src
family members are associated with different receptors and
phosphorylate distinct but overlapping sets of downstream target molecules. For example, Lck, Lyn, and Fyn can be activated
by IL-2 (29, 32).
The Jak family of kinases comprises four known relatively
large proteins (Jak1, Jak2, Jak3, and Tyk2) that can bind cytokine receptor subunits, phosphorylate them, and in doing so
creat docking sites on the receptors for binding of SH2-containing proteins (33, 34). In general, Jaks consist of several domains
(JH1-JH7) of which the functional significance has been characterized by mutational analysis and include a TK domain (JH1;
Refs. 3, 33, 35, 36). The precise functions of JH2-JH7 domains
are under current investigation (3). Jaks are able to associate
with the cytokine receptors as well as with each other (37, 38).
Dimerization/oligomerization of cytokine receptor subunits as a
result of ligand binding leads to juxtaposition of Jaks (3). This
results in transphosphorylation and activation of their kinase
activity and the phosphorylation of downstream signaling proteins such as Stats, Src-kinases, and adaptors such as Shc, Grb2,
and Cbl (Fig. 1; Refs. 39, 40).
Abnormalities of Jak function have been associated with a
number of disorders (34, 41). For example, chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of Stat5, IL-3-independent cellular proliferation, and leukemogenesis (42, 43). The translocation
t(9;12)(p24;p13) results in the fusion of the kinase catalytic
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 537
region of JAK2 with the transcription factor TEL generating the
constitutively active TEL-JAK2. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type
I, and Abelson murine leukemia viruses results in enhanced TK
activity of Jaks, possibly accounting for their leukemogenic
potential (44, 45).
The Stat transcription factors are coded by six known
mammalian genes and include 10 different Stat proteins including different isomers of Stats 1, 3, 4, and 5 (3, 46). Like other
transcription factors Stats have a well-defined structure including a DNA-binding domain, a conserved NH2-terminal domain,
a COOH-terminal transactivation domain, and SH2 and SH3
domains (3). Their activation through tyrosine phosphorylation
results in their dimerization and translocation into the nucleus
where they activate specific genes (6, 47– 49).
Jak proteins activate a number of intracellular signaling
proteins, among which Stats are the best defined (46, 50).
Binding of a cytokine to its receptor rapidly induces tyrosine
phosphorylation of the cytoplasmic domains of the receptor by
activated Jak kinases, thus providing a docking site for Stat
proteins, which are then phosphorylated. This phosphorylation
of Stats leads to their homo- or heterodimerization and translocation to the nucleus, followed by DNA binding and gene
activation (Fig. 1; Refs. 51, 52). The specificity for Stat phosphorylation is determined by the receptor docking sites and not
the Jak kinases (53, 54). Also, different Stat proteins have
different DNA-binding affinities, resulting in activation of specific genes. Stats also interact with other transcription factors
such as the p300/cyclic AMP-responsive element binding protein family of coactivators to activate genes (55, 56). The
transcriptional activity of Stats may also be regulated by the
phosphorylation of their serine and threonine residues, although
the implications of such regulation are not known (7, 57).
Stats mediate diverse and sometimes opposite cellular
events affecting growth, differentiation, and apoptosis (58, 59).
For example, Stats can mediate both growth arrest and cellular
proliferation. Specifically, Stat1 mediates the growth-inhibitory
effects of IFN-␥, through the induction of the CDKI p21waf1,
whereas Stat5 mediates proliferative effects of IL-3 and GMCSF (60, 61). Similarly, phosphorylation of Stat3 can result both
in IL-6- and IL-10-induced growth arrest, and in GM-CSF- and
IL-3-induced proliferation (61– 63). Stats also modulate cellular
differentiation and apoptosis. Reconstitution of Stat1 in Stat1null U3A cells (which do not respond to TNF-␣) restores basal
caspase expression and renders them sensitive to TNF-induced
apoptosis (64). Conversely, Stat3 and Stat5 mediate the antiapoptotic effects of IL-6 and IL-2, respectively (65, 66). Stat1
activates the caspase cascade through up-regulation of Fas and
FasL expression in response to IFN-␥ (67). The exact mechanisms underlying these diverse effects are being elucidated.
An important property of cellular signaling pathways is
that their activation is both rapid and transient. This is because
of effective mechanisms of inactivation. In the Jak-Stat system,
proteasome-mediated degradation, tyrosine dephosphorylation,
and inhibition by various inhibitory proteins are responsible for
this process (4). The ubiquitin-proteasome pathway governs the
degradation of many intracellular proteins including activated
Stats, and effective inhibitors of this system have shown promising early results in clinical trials (68, 69). The cytokine-
activated Jak-Stat pathways are also inhibited by tyrosine dephosphorylation mediated by cytoplasmic phosphatases such as
SHP-1 (70, 71). SHP-1-deficient mice demonstrate multiple
hematopoietic abnormalities, including hyperproliferation and
abnormal activation of granulocytes and macrophages in the
lungs and in the skin (72). SOCS and PIAS are other important
inhibitors of the activated Jaks and Stats (70, 73). Recent studies
have established that SOCS are negative regulators of cytokines,
and there is ample evidence suggesting the importance of Stats
in the induction of SOCS expression, thereby constituting a
negative feedback mechanism (74 –76). The role of these inhibitory proteins in the pathogenesis of neoplastic transformation is
also becoming clearer (77).
RTK and Serine/Threonine Signaling Pathways
RTKs are membrane-bound enzymes with an extracellular
ligand-binding domain, a transmembrane domain, and a highly
conserved intracellular domain that mediates the activation,
through tyrosine phosphorylation, of a number of downstream
signaling proteins (78 – 80). These enzymes are activated by
ligand binding, by cell-cell interactions via cell adhesion molecules, and by stimulation of G-protein coupled receptors (81).
Phosphorylated tyrosine residues in specific domains of these
receptors serve as high-affinity docking sites for SH2-containing adaptor and effector proteins (82). RTKs include diverse
molecules, which are considered as members of several distinct
classes: class I including epidermal growth factor receptor; class
II including insulin-like growth factor-1 receptor; class III
including PDGFR, macrophage colony-stimulating factor
(FMS-R or CSF-1R), stem cell factor receptor (KIT), and
FLT3R; and class IV including FGFR (79, 83, 84). The importance of these receptors in malignant transformation and the
possibility of modulating them as therapeutic targets are subjects of intense research. The recent reports of constitutive
activation of FLT3R resulting in stimulation of multiple signaling pathways and leading to malignant transformation has been
of significant interest in leukemia research (85, 86). Such constitutive activation of this receptor has been reported in ⬎30%
of patients with AML and results from two well-described
molecular events. Internal tandem duplication mutations of
FLT3R gene occur at exons 11 and 12 of the gene that code for
the juxtamembrane domain of receptor (87–90). More recently,
point mutations of codon 835 of FLT3R receptor gene, located
in the activation loop of its TK domain, have been reported in
7% of patients with AML (87, 91). Inhibitors of such aberrant
activation are undergoing clinical evaluation (92, 93).
Many intracellular signaling proteins bind the phosphotyrosine on the activated RTKs. These proteins include GTPase
activating protein, PI3K, Grb2, and Src-like tyrosine-kinases (1,
10, 78). The activation of these proteins by serine/threonine
phosphorylation in turn activates a number of downstream signaling cascades that lead to gene transcription (10).
Although knowledge of the Jak-Stat pathway has been
instrumental in understanding cytokine signaling (94), the importance of signaling cascades that involve the activation of
serine/threonine kinases is increasingly apparent (10). The serine/threonine MAPKs, which include the Ras-Raf-MEK-ERK
pathway, the p38 family of kinases, and the JNK (SAPK)
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
538 Cellular Signaling Pathways as Therapeutic Targets
family, are activated by upstream signals and mediate effects on
inflammation, cell growth, cell cycle progression, cell differentiation, and apoptosis (95). The Ras family of proteins belongs
to the large superfamily of GTPases that localize to the inner
surface of the plasma membrane (1, 96). Ras proteins play a
pivotal role in a number of signaling pathways mediated by
RTKs and other receptors. Ligand binding to these receptors
initiates the autophosphorylation of specific tyrosine residues in
their cytoplasmic domain and creates phosphotyrosyl-binding
sites for adapter proteins such as Shc and Grb2, which in turn
recruit guanine nucleotide exchange factors and thereby initiate
Ras activation (97, 98).
Once induced, Ras activates Raf serine/threonine kinase,
which then phosphorylates MAPK kinases (otherwise known as
MEKs; Refs. 10, 97, 99). These in turn activate MAPKs (or
ERKs; Refs. 100, 101), which in turn move to the nucleus where
they phosphorylate and activate nuclear transcription factors
such as Elk-1 (102). ERKs were initially described as a novel
family of protein kinases that, when activated, produced proliferative stimuli (103). ERKs can also activate other kinases such
as RSKs (also known as MAPK-activated protein kinases),
which are involved in cell-cycle regulation and apoptosis (104).
ERK-activated RSK kinase catalyzes the proapoptotic protein
Bad and suppresses Bad-mediated apoptosis (105). Similarly,
the Ras-Raf-MEK-ERK cascade modulates cellular proliferation by regulating the activity of several proteins, including
cell-cycle regulators (e.g., cyclin D1, p21waf1/cip1, p27kip1, and
cdc25A) and transcription factors (e.g., c-Myc; Ref. 106).
The G1/S cell cycle checkpoint is a critical point determining the commitment of cells to growth arrest or proliferation.
During this stage cells are responsive to cytokines (107). Regulatory proteins p21waf1/cip1 and p27kip1 are of particular importance in this transition, which is controlled by both positive and
negative regulators. Distinct Rb-E2F repressor complexes suppress the transcription of genes required for progression of
various phases of cell cycle. For example, Rb-E2F1 complex
suppresses the progression through G1 (108). During this progression from G1 to S-phase cyclin/CDKs are sequentially activated, which then inactivate suppressor complexes such as
Rb-E2F1 (109). Cyclin/CDK activity results in Rb phosphorylation and its dissociation from E2F1 leading to activation of
genes necessary for S phase (110). Activity of a number of these
cyclin/CDKs as well their inhibitors such as p21waf1/cip1 is modulated by cytokine-mediated signals through their phosphorylation.
The p38 family of MAPKs is involved in various cellular
processes such as inflammation, cell cycle progression, and cell
death (111, 112). The four different p38 isoforms (␣, ␤, ␥, and
␦) are activated by two MEK isoforms (113). Originally, the p38
kinase pathway was reported to have a critical role in the
generation of signals in response to stress stimuli. However, its
role in cytokine signaling and regulation of the Jak-Stat pathway
has been elucidated recently (114). In particular, from the standpoint of leukemogenesis, it modulates the growth-inhibitory
effect of type I IFNs in BCR-ABL-expressing cells as well as
normal hematopoietic progenitors (115, 116).
The third group of MAPKs includes the JNK (otherwise
known as SAPK; Ref. 95). The four different JNK kinases have
a similar role to p38 kinases in cellular function and are acti-
vated by specific MAPK kinases (MEKKs) in response to
inflammatory cytokines such as TNF-␣, and other stress stimuli
such as reactive oxygen species, heat, and withdrawal of growth
factors (117). The MEKK1/JNK signaling increases p53 stability and transcriptional activation, and MEKK1/JNK potentiates
the ability of p53 to initiate apoptosis (118).
Normal functioning of MAPK-mediated signaling necessitates its efficient inactivation (95). A number of dual-specificity
MAPK phosphatases serve to dephosphorylate and, hence, inactivate MAPKs (119 –121). Similarly, protein phosphatases
PP1 and PP2 dephosphorylate and inactivate a number of phosphoproteins including components of the MAPK pathway
(122, 123).
Other signaling pathways such as those mediated by PI3K,
AKT (also known as PKB), and protein kinase C are also
controlled by serine/threonine phosphorylation (Fig. 2; Ref. 10).
PI3K consists of two subunits, the p85 regulatory subunit and
the p110 catalytic subunit (124, 125). The p85 subunit binds to
the cytokine receptor as a consequence of ligand-receptor interaction and receptor autophosphorylation (126). As a result,
phosphatidylinositol-dependent kinases and their downstream
substrate AKT/PKB are recruited to the membrane (127). PI3KAKT pathway activates several downstream targets including
p70 RSK, forkhead transcription factors, and NF␬B (128 –130).
The serine/threonine kinase AKT is an important component of
the cell survival machinery (10, 131–133). Its activation via the
PI3K pathway leads to a number of events (10, 131, 134, 135).
For example, the phosphorylation of the cytosolic protein I␬B
by AKT releases NF␬B from its association with I␬B. NF␬B
then moves into the nucleus, where it induces a number of genes
involved in cell survival (131). Meanwhile, the inhibitory protein I␬B is degraded by the proteasome (136). AKT also phosphorylates the proapoptotic protein Bad, which leads to higher
levels of free antiapoptotic Bcl-xL and thereby inhibits the
cell-death protease caspase-9 (134). The tumor suppressor gene
PTEN codes for a phosphatase that acts by removing a phosphate group from the 3 position of the inositol ring of the
PIP3,4,5 phospholipids located at the cellular membrane. This
prevents the proximation of AKT and phosphatidylinositoldependent kinases, and prevents AKT activation (137–140).
Several lines of evidence including studies of PTEN knockout
mice support the role of PTEN as a tumor suppressor gene (141).
Serine/threonine kinases, in general, also influence the activity
of other antiapoptotic proteins of the Bcl-2 family (10, 135,
142). In the normal cell cycle, Bcl-2 is phosphorylated on its
serine/threonine residues at several points during the G2 to M
phase transition (10, 143).
PKC, another important signaling enzyme, phosphorylates
specific serine or threonine residues on target proteins in different ways (Fig. 2). For example, PKC is a potent activator of
Raf-1, which activates the MAPK cascade. This leads to phosphorylation of I␬B, release of NF␬B, translocation of NF␬B into
the nucleus, and gene transcription as described above (144 –
146). PKC also regulates cytokine signals through its effects on
the Jak-Stat pathway in some myeloid progenitor cell lines
(147). The significant role of PKC in phosphorylation and
activation of Raf has led to its targeting for inhibition of the
Raf-Ras-MEK-ERK pathway (95, 148). For example, stauros-
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 539
Fig. 2 Interactions of diverse signaling pathways.
porine analogs UCN-O1 and CGP 41251 are being examined as
inhibitors of PKC and MAPK signaling (149, 150).
Various signaling pathways interact resulting in their modulation at several levels. For example, PI3K interacts with and
enhances Raf-Ras-MEK-ERK pathway (151–153). Other serine/threonine phosphorylation pathways modulate cytokine signals through the Jak-Stat pathway (10, 154). In addition to being
tyrosine phosphorylated, several Stats (Stat1␣, Stat3, and Stat4)
are serine phosphorylated by ERKs at conserved serine residues
(155). In fact, during cytokine signaling, Jak and Raf kinases
carry on an intricate cross-talk (10).
Therapeutic Implications
Signaling pathways may be particularly attractive targets in
cancer therapy because they may be inappropriately activated in
malignant cells. However, several factors must be carefully
considered while developing agents that modulate these pathways. One is the possible toxicity of such therapy. Because
these pathways are activated to a significantly greater degree in
malignant cells than normal cells, their partial inhibition may be
sufficient to interfere with malignant cell growth without causing significant toxicity (25). Therefore, despite the pivotal role
of these pathways in normal cellular function, their inhibition
may not be toxic to normal cells.
Another point of consideration in designing inhibitors is
the specificity of the target pathway and the selectivity of its
inhibitors. Adding to this challenge is the fact that these pathways are part of a complex network of interconnecting cascades
resulting in a certain degree of redundancy and overlap.
Diseases induced by specific oncogenic alterations leading
to constitutive activation of pivotal molecules in the pathways
may provide us with such specificity and selectivity. A number
of translocations occurring in hematological malignancies are
known to result in fusion genes with enhanced kinase activity
(24). The oncoprotein Bcr-Abl results from a translocation be-
tween chromosomes 9 and 22, and occurs in CML and ALL. Its
transforming activity is the product of activation of a number of
signaling molecules such as Ras, Raf, PI3K, JNK/SAPK, Crkl,
and Stat5 (156 –160). As a result of their activation, a number of
pathways, which inhibit apoptosis and promote cell survival, are
induced (24). Bcr-Abl is constitutively phosphorylated on a
number of tyrosine residues, allowing the docking of adaptor
proteins such as Cbl, Crkl, Shc, and Grb2, which recruit the Ras
signaling pathway, the p85 regulatory subunit of PI3K, the focal
adhesion proteins paxillin and talin, and a number of other
signaling pathways (159, 161–163). The specific Bcr-Abl inhibitor Imatinib mesylate has proven to be very effective in suppressing these pathways in vitro and in patients with CML and
ALL (164 –170).
Although the platelet-derived growth factors, PDGFR␣
and PDGFR␤ have significant homology, only the PDGFR␤ has
been implicated in hematological cancers where a significant
number of patients with chronic myelomonocytic leukemia have
t(5;12)(q33;p13) generating the fusion protein TEL-PDGFR␤
(171, 172). As a result of ligand-independent dimerization and
autophosphorylation of the PDGF ␤-subunit, the TK is constitutively active. PDGF is able to stimulate the growth of primitive hematopoietic, erythroid, and megakaryocytic precursors,
and TEL-PDGFR␤ can confer cytokine-independent growth to
Ba/F3cells (173). Imatinib mesylate inhibits the kinase
PDGFR␤ and has been shown anecdotally to be effective in
patients with this translocation (174).
Similarly, the chimeric gene NPM-ALK is produced as a
result of translocation t(2;5)(p23;q35; Refs. 175, 176). Fusion of
NH2-terminal domain of NPM to the cytoplasmic region of the
ALK TK receptor results in constitutive activation of its catalytic domain (177, 178). NPM-ALK associates with a number of
adaptor proteins such as Grb2 and Crkl, and results in the
activation of the downstream signaling proteins such as PI3K,
AKT, and Stat5 (179 –182). Therefore, design of specific inhib-
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
540 Cellular Signaling Pathways as Therapeutic Targets
Fig. 3 Targets for inhibition in Jak-Stat signaling pathway.
itors of the NPM-ALK may be of considerable interest in
treating patients with anaplastic large cell lymphoma where up
to 50% of patients express the chromosomal translocation (183).
The TK modulated pathways such as the Jak-stat cascade
can be targeted at several steps along the way (Fig. 3). Because
a number of cytokines and growth hormones play an important
role in the suppression of apoptosis in the malignant clone in
hematological cancers (e.g., IL-6 in myeloma; IL-2 in some
T-cell lymphomas; and IL-1, IL-3, and GM-CSF in AML; Refs.
25, 184), inhibition of the cytokines and their receptors is a
plausible therapeutic strategy (185, 186). Furthermore, where
there is constitutive activation of the receptor leading to neoplastic change, selective inhibition of kinase activity of the
receptor is likely to be of benefit. For example, inhibition of
FLT3-R TK activity is selectively cytotoxic to AML blasts
harboring the appropriate activating mutations (92, 187). Activating mutations of FLT3-R including the internal tandem duplication mutation and mutation of the TK domain occur in
⬎30% of patients with AML, confer adverse prognosis, and can
be targeted by selective inhibitors (92, 188, 189). Clinical trials
examining the efficacy and safety of such inhibitors are currently under way. Intracellular activators of Stats such as Jaks
and Src are also likely targets (164 –166). For example, the Jak2
inhibitor AG490 inhibited the growth of ALL cells in a mouse
model without affecting normal hematopoiesis (190). AG490
also acts by inhibiting Stat function, and induces apoptosis in
Sezary cells and myeloma cells (191, 192). Furthermore, numerous other cellular TKs have been identified that likely have
roles in neoplastic cell survival and proliferation, and a number
of TK inhibitors are already being explored for their effects on
signaling cascades. In general, two classes of TK inhibitors are
being developed: inhibitors of the ATP binding site and inhibitors of the substrate binding sites (164, 193, 194).
There are other ways to interrupt Stat signaling. One is the
specific inhibition of the Stat SH2 domain, because it is essential
for the recruitment of Stats to the receptor subunit and for Stat
dimerization (25). Antisense oligonucleotides directed at Stats
(195), modulation of the activity of natural Stat inhibitors such
as SOCS and PIAS, and inhibition of the binding of activated
Stat dimers to their DNA targets (25, 196, 197) are other
mechanisms currently under investigation.
A better understanding of the effects of current antineoplastic agents on these pathways may also elucidate their mechanism of action and lead to the development of more effective
and less toxic agents. For example, fludarabine causes a profound and specific loss of Stat1 (198), which may be at least
partly responsible for its antineoplastic properties as well as its
immunosuppressive properties, which is similar to Stat1 knockout mice.
Multiprotein complexes, which can modify the structure of
chromatin and influence gene regulation, are often aberrant in
hematological malignancies. Although their interactions with various signaling pathways have not been clearly defined, they merit
specific mention as they are subject of intense research. Such
complexes include proteins such as HDAC, histone acetyltransferase, and DNA methyltransferases. In a significant proportion of
patients with AML-M2, the translocation t(8;21)(q22;q22) results
in the fusion of the DNA-binding domain of AML1 with ETO,
which interacts with corepressor complexes such HDAC and repress cellular differentiation (199, 200). Similarly, t(12;21)(p13;
q22) in childhood ALL results in recruitment of the repressor
N-CoR by the fusion protein TEL-AML1 (201, 202). Inhibitors of
HDACs and DNA methyltransferase such as butyrates, trichostatin
A, 5-azacytidine, and 2⬘-deoxy-azacytidine are currently under
investigation in clinical trials (203, 204).
The most common translocation in APL, t(15;17)(q22;
q11.2), results in the fusion of RAR␣ with the PML genes, with
the resulting fusion protein retaining the functional domains of
both (205, 206). The fusion protein recruits nuclear receptor
corepressors SMRT and N-CoR, which together with HDACs
keep the chromatin in the closed configuration and suppress/
inactivate retinoid receptor target genes in myeloid development
(207, 208). In patients with PML-RAR␣, pharmacological doses
of ATRA can convert the fusion protein from a dominantnegative inhibitor of retinoid-regulated transcription to an
activator (209). Signaling pathways that interact with retinoidmediated transcription may be modulated to potentiate ATRAinduced differentiation (210). ATRA may also exert effects on
upstream signaling pathways. For example, ATRA up-regulates
Stat1 and Stat2 activity in the IFN-␣ signaling pathway, thereby
potentiating the growth-inhibitory effects of IFN-␣ (211–213).
Another novel therapeutic agent in APL, arsenic trioxide, affects
a number of cellular signaling pathways, leading to induction of
apoptosis and differentiation (214 –217). Therapeutic effects
of arsenic trioxide in APL are partly related to its degradation of
PML-RAR␣ fusion protein through targeting PML to proteasomal degradation by Sumolation (218). However, arsenic trioxide
has a number of other effects such as activation of JNK kinases;
translocation of PKC from cytosol to plasma membrane to
mediate downstream signaling; enhancement of CDKIs,
p21waf1/cip1, and p27kip1; and inhibition of I␬B kinase and NF␬B
(214).
Monoclonal antibodies such as rituximab (anti-CD20) and
alemtuzumab (anti-CD52) are increasingly used in treating hematological malignancies (219 –221). Their exact mechanism of
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 541
Fig. 4 Targets for inhibition in RTK signaling pathways.
action is largely unknown. However, understanding their effects
on the signaling pathways downstream of the target receptor is
likely to point the way to more effective agents. The ligation of
CD20 by rituximab in the presence of FcR-expressing cells may
initiate signal transduction events that induce an elevation of
intracellular Ca2⫹ and lead to apoptosis of the target malignant
B cells (222). Rituximab has also been shown in vivo to activate
caspases in blood leukemia cells immediately after its infusion
suggesting a mechanism of action independent of complementmediated cell lysis or antibody-dependent cellular cytotoxicity
(223, 224).
Inhibition of serine/threonine kinases involved in RTK
signaling is another major area of research and development. As
noted previously, Ras proteins play a significant role in human
carcinogenesis. Therefore, inhibition of Ras signal transduction
has been the subject of intense research. Ras-mediated signaling
can be inhibited by prevention of its membrane localization, by
inhibition of Ras protein expression using antisense nucleotides,
and by inhibition of its downstream targets (95, 225). Pharmacological inhibitors of farnesyltransferase, the enzyme responsible for the COOH-terminal prenylation of Ras and, hence, its
membrane association and transforming activity, have already
been developed, and clinical trials of their efficacy in leukemia
are under way (96, 226 –229). Four such farnesyl transferase
inhibitors are available at various stages of testing: R115777,
SCH66336, L778123, and BMS214662 (95, 230, 231). FTIs
may also have Ras-independent effects on other cellular signaling components that contribute to their antineoplastic action
(232). Other steps in the serine/threonine cascades, from the cell
surface receptor to gene transcription, are also being examined
as possible targets for therapy (Ref. 95; Fig. 4). Compounds
such as geldanamycin and derivatives of radicicol are known to
destabilize Raf protein and interfere with Raf signaling (233–
235). Several staurosporine derivatives including UCN-O1,
CGP41251, and PKC412 are able to inhibit PKC signaling, and
have been examined in cell lines and clinical studies (149, 150,
236). Aberrant MEK and ERK activity has been demonstrated
in AML and CML (237–240), and MEK inhibitors such as
PD098059, PD184352, and UO126 are able to modulate cellular proliferation, differentiation, and apoptosis (241–243).
PD184352 has been examined in Phase I trials in patients (244).
Pharmacological inhibitors of PI3K, wortmannin, and
LY294002 have shown significant potency in preclinical studies
(245, 246).
Downstream targets of these signaling pathways involved
in cell-cycle regulation, cell survival, and apoptosis can also be
modulated (Table 1). For examples, agents capable of promoting apoptosis are being developed (247). These may function by
activating the caspase cascade through blockade of the IAPs,
inhibition of the NF␬B pathway (using I␬B kinase inhibitors or
proteasome inhibitors), and inhibition of the PI3K pathway
(using kinase inhibitors; Refs. 69, 134, 248). IAPs including the
XIAP can block the process of programmed cell death through
their interaction with members of the caspase family of cysteine
proteases (249). The human family of caspases includes 11
members involved in processing of inflammatory cytokines as
well as execution of apoptosis (250). Dysregulation of caspase
cascade has been implicated in human neoplasia, and IAPs, the
natural inhibitors of caspases, are pivotal in this regulatory
process (250, 251). XIAP, the most potent member of the IAP
family blocks both the initiator caspase-9, and the effector
caspases-3 and -7 (252). An association between XIAP levels
and survival has been reported in AML (253). Down-regulation
of XIAP protein by adenoviral antisense vector results in sensitization to radiation-induced cell death (254).
The ubiquitin-proteasome pathway is the central pathway
for degradation of intracellular proteins (255, 256). Targeting
of proteins to proteasome is through covalent attachment of
a poly-ubiquitin chain. This system is specific allowing upregulation of degradation of certain proteins without affecting
the proteolysis of other substrates; this enables the proteasome
to function as a regulator of metabolic pathways (256). Therefore, different classes of proteasome inhibitors can be used to
differentially affect cellular levels of oncogenic proteins (256).
Important substrates for proteasome degradation include cyclins
and CDKIs; transcription factors such as p53, NF␬B, c-Myc,
c-fos, and c-Jun; a number of apoptosis family of proteins; IAPs;
and some caspases (256 –262). PS-341 is a specific and potent
inhibitor of proteasome (263). It induces apoptosis and overcomes resistance in a number of cell lines as well as primary
cells from patients with chronic lymphocytic leukemia (264 –
268). Its in vitro activity in myeloma has led to its ongoing
examination in clinical trials (269 –271).
Cell-cycle proteins such as the CDKs and their inhibitors
(CDKIs), which modulate cell-cycle progression in response to
appropriate signals, are also possible targets. Orderly cell division requires a tight control of cyclins and CDKs, particularly at
the G1/S checkpoint (272). Complexes of Rb family of tumor
suppressors with E2F transcription factors inhibit the transcription of several genes involved in the S phase of cell cycle both
by active repression as well as through the recruitment of
HDACs (273, 274). Phosphorylation of Rb by cyclin/CDK
complexes leads to release of E2Fs and transactivation of target
genes by binding of E2Fs to E2F response elements (275). The
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
542 Cellular Signaling Pathways as Therapeutic Targets
Table 1
Targets for drug development
Target
Prototype drug
Mode of action
Tyrosine and serine/threonine kinases
Rituxan, Campath-1H
CEP-701, AG1295
Genistein
Limonene, perillyl alcohol, R115777, SCH66336,
L778123, BMS214662
Geldanamycin, radicicol
Wortmannin, LY294002
Rapamycin
PD098059, PD184352, UO126
AG490
Imatinib mesylate
Flavopiridol, Olomoucine, UCN-01
Purvalanol
Staurosporine, UCN-O1, CGP41251, PKC412
Bryostatin
—
PS341
Suramin, SU5416
Anthraquinones
Ligand-binding inhibition
FLT3R kinase inhibition
Non-specific kinase
Ras FT inhibitiona
Cell-cycle proteins
Apoptosis-related proteins
Angiogenesis-related proteins
Cell life span targets
Transcription factors (Myc, Ets, Fos,
Jun, Rel, Myb)
Raf inhibition
PI3K inhibition
P70S6K inhibition
MEK inhibition
JAK inhibition
ABL, PDGFR, KIT
CDK inhibition
Cdc2 inhibition
Bcl-2 inhibition (PKC)
PKC activation
P53-MDM2 inhibition
Proteasome inhibition
VEGFR and bFGFR
Telomerase inhibition
a
Ras FT, Ras farnesyl transferase; MDM2, mouse double minute-2; PKC, protein kinase C; VEGFR, vascular endothelial growth factor receptor;
bFGFR, basic fibroblast growth factor receptor.
activity of cyclin D:CDK4/6 and cyclin E:CDK2 complexes is
regulated by CDKIs of the INK4 and KIP families such as
p16ink4a, p15ink4b, p18ink4c, p19ink4d, p21waf1/cip1, p27kip1, and
p57kip2, which act as inhibitors of G1/S transition. Disrupted
activity of a number of G1 checkpoint genes/proteins has been
implicated in carcinogenesis (275). Decreased Rb expression,
and a negative correlation between Rb expression and survival
have been reported in ALL (276). Deletions and mutations of Rb
have been reported in a number of hematological malignancies
(276). Genes for p16ink4a and p15ink4b are suppressed in various
hematological cancers mainly by deletion and by hypermethylation of their promoters (277, 278). The role of inactivation of
these genes as a prognostic indicator has been controversial
(275). Alternatively, oncogenic amplification, and overexpression of cyclins and CDKs have been reported in a number
of hematological cancers (279). Of note are overexpression
of cyclin D1 in mantle cell lymphoma and hyperactivation of
cdk4/cdk6 in human T-cell leukemia virus type 1 leukemias
(279). Inhibitors of cyclins and CDKs such as flavopiridol, and
the staurosporine derivative UCN-01 are under active development (248, 280). Early phase clinical trials of these agents have
been reported recently (279, 281). However, it is likely that the
majority these drugs will be used in combination with standard
cytotoxic chemotherapy agents or for therapy of minimal residual disease.
Concluding Remarks
Over the past decade extensive research has elucidated the
role of cellular signaling pathways in cellular growth, differentiation, and apoptosis. The disruption of these pathways, on the
other hand, has been shown to promote the neoplastic transformation of cells. This knowledge has led to the development of
a number of molecules that in preclinical and clinical studies
have been shown to be capable of reversing the neoplastic
process. Our current challenge is to further understand the
complexity of these processes and to devise specific agents that
target the neoplastic cells whereas sparing normal tissues. This
would truly realize the concept of targeted therapy in treating
hematological malignancies and solid tumors alike.
References
1. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson,
J. D. Molecular Biology of the Cell, Ed. 3, pp. 721–785. New York,
London: Garland Publishing Inc., 1994.
2. Kishimoto, T. The biology of interleukin-6. Blood, 74: 1–10, 1989.
3. Rane, S. G., and Reddy, E. P. JAKs. STATs and Src kinases in
hematopoiesis. Oncogene, 21: 3334 –3358, 2002.
4. Shuai, K. The STAT family of proteins in cytokine signaling. Prog.
Biophys. Mol. Biol., 71: 405– 422, 1999.
5. Ihle, J. N., Thierfelder, W., Teglund, S., Stravapodis, D., Wang, D.,
Feng, J., and Parganas, E. Signaling by the cytokine receptor superfamily. Ann. N. Y. Acad. Sci., 865: 1–9, 1998.
6. Darnell, J. E., Jr., Kerr, I. M., and Stark, G. R. Jak-STAT pathways
and transcriptional activation in response to IFNs and other extracellular
signaling proteins. Science (Wash. DC), 264: 1415–1421, 1994.
7. Decker, T., and Kovarik, P. Transcription factor activity of STAT
proteins: structural requirements and regulation by phosphorylation and
interacting proteins. Cell Mol. Life Sci., 55: 1535–1546, 1999.
8. Cooper, J. A., and Howell, B. The when and how of Src regulation.
Cell, 73: 1051–1054, 1993.
9. Pawson, T. Protein modules and signalling networks. Nature (Lond.),
373: 573–580, 1995.
10. McCubrey, J. A., May, W. S., Duronio, V., and Mufson, A. Serine/
threonine phosphorylation in cytokine signal transduction. Leukemia
(Baltimore), 14: 9 –21, 2000.
11. Pratt, J. C., Weiss, M., Sieff, C. A., Shoelson, S. E., Burakoff, S. J.,
and Ravichandran, K. S. Evidence for a physical association between
the Shc-PTB domain and the ␤ c chain of the granulocyte-macrophage
colony-stimulating factor receptor. J. Biol. Chem., 271: 12137–12140,
1996.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 543
12. Okuda, K., Sanghera, J. S., Pelech, S. L., Kanakura, Y., Hallek, M.,
Griffin, J. D., and Druker, B. J. Granulocyte-macrophage colony-stimulating factor, interleukin-3, and steel factor induce rapid tyrosine phosphorylation of p42 and p44 MAP kinase. Blood, 79: 2880 –2887, 1992.
13. Coffer, P. J., Geijsen, N., M’Rabet, L., Schweizer, R. C., Maikoe,
T., Raaijmakers, J. A., Lammers, J. W., and Koenderman, L. Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function. Biochem. J., 329: 121–130, 1998.
14. Itoh, T., Muto, A., Watanabe, S., Miyajima, A., Yokota, T., and
Arai, K. Granulocyte-macrophage colony-stimulating factor provokes
RAS activation and transcription of c-fos through different modes of
signaling. J. Biol. Chem., 271: 7587–7592, 1996.
15. Nagata, Y., Moriguchi, T., Nishida, E., and Todokoro, K. Activation of p38 MAP kinase pathway by erythropoietin and interleukin- 3.
Blood, 90: 929 –934, 1997.
16. Nagata, Y., Nishida, E., and Todokoro, K. Activation of JNK
signaling pathway by erythropoietin, thrombopoietin, and interleukin-3.
Blood, 89: 2664 –2669, 1997.
17. Foltz, I. N., and Schrader, J. W. Activation of the stress-activated
protein kinases by multiple hematopoietic growth factors with the exception of interleukin-4. Blood, 89: 3092–3096, 1997.
18. Terada, K., Kaziro, Y., and Satoh, T. Ras-dependent activation of
c-Jun N-terminal kinase/stress-activated protein kinase in response to
interleukin-3 stimulation in hematopoietic BaF3 cells. J. Biol. Chem.,
272: 4544 – 4548, 1997.
19. Coffer, P. J., Schweizer, R. C., Dubois, G. R., Maikoe, T.,
Lammers, J. W., and Koenderman, L. Analysis of signal transduction
pathways in human eosinophils activated by chemoattractants and
the T-helper 2-derived cytokines interleukin-4 and interleukin-5.
Blood, 91: 2547–2557, 1998.
20. Tilton, B., Andjelkovic, M., Didichenko, S. A., Hemmings, B. A.,
and Thelen, M. G-Protein-coupled receptors and Fc␥-receptors mediate
activation of Akt/protein kinase B in human phagocytes. J. Biol. Chem.,
272: 28096 –28101, 1997.
21. Songyang, Z., Baltimore, D., Cantley, L. C., Kaplan, D. R., and
Franke, T. F. Interleukin 3-dependent survival by the Akt protein kinase.
Proc. Natl. Acad. Sci. USA, 94: 11345–11350, 1997.
22. Sato, N., Sakamaki, K., Terada, N., Arai, K., and Miyajima, A.
Signal transduction by the high-affinity GM-CSF receptor: two distinct
cytoplasmic regions of the common ␤ subunit responsible for different
signaling. EMBO J., 12: 4181– 4189, 1993.
23. Calvo, V., Wood, M., Gjertson, C., Vik, T., and Bierer, B. E.
Activation of 70-kDa S6 kinase, induced by the cytokines interleukin-3
and erythropoietin and inhibited by rapamycin, is not an absolute
requirement for cell proliferation. Eur. J. Immunol., 24: 2664 –2671,
1994.
24. Scheijen, B., and Griffin, J. D. Tyrosine kinase oncogenes in normal
hematopoiesis and hematological disease. Oncogene, 21: 3314 –3333,
2002.
25. Frank, D. A. STAT signaling in the pathogenesis and treatment of
cancer. Mol. Med., 5: 432– 456, 1999.
26. Metcalf, D. The molecular control of cell division, differentiation
commitment and maturation in haemopoietic cells, Nature (Lond.), 339:
27–30., 1989.
27. Taniguchi, T. Cytokine signaling through non-receptor protein tyrosine kinase. Science (Wash. DC), 268: 251–255, 1995.
28. Hunter, T. Signal transduction. Cytokine connections. Nature
(Lond.), 366: 114 –116, 1993.
29. Stahl, N., and Yancopoulos, G. D. The ␣s, ␤s, and kinases of
cytokine receptor complexes. Cell, 74: 587–590, 1993.
30. Kishimoto, T., Taga, T., and Akira, S. Cytokine signal transduction.
Cell, 76: 253–262, 1994.
31. Carpenter, L., Yancopoulos, G., and Stahl, N. General mechanisms
of cytokine receptor signaling. Adv. Protein Chem., 52: 109 –140, 1999.
32. Kobayashi, N., Kono, T., Hatakeyama, M., Minami, Y., Miyazaki,
T., Perlmutter, R. M., and Taniguchi, T. Functional coupling of the
src-family of kinases p59fyn and p53/56lyn with the interleukin 2
receptor: Implications for redundancy and pleiotropism in cytokine
signal transduction. Proc. Natl. Acad. Sci. USA, 90: 4201– 4205, 1993.
33. Yeh, T. C., and Pellegrini, S. The Janus kinase family of protein
tyrosine kinases and their role in signaling. Cell. Mol. Life Sci., 55:
1523–1534, 1999.
34. Ward, A. C., Touw, I., and Yoshimura, A. The Jak-Stat pathway in
normal and perturbed hematopoieis. Blood, 95: 19 –29, 2000.
35. Zhao, Y., Wagner, F., Frank, S. J., and Kraft, A. S. The aminoterminal portion of the JAK2 protein kinase is necessary for binding and
phosphorylation of the granulocyte-macrophage colony- stimulating
factor receptor ␤ c chain. J. Biol. Chem., 270: 13814 –13818, 1995.
36. Saharinen, P., Takaluoma, K., and Silvennoinen, O. Regulation of
the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol.,
20: 3387–3395, 2000.
37. Livnah, O., Stura, E. A., Middleton, S. A., Johnson, D. L., Jolliffe,
L. K., and Wilson, I. A. Crystallographic evidence for preformed dimers
of erythropoietin receptor before ligand activation. Science (Wash. DC),
283: 987–990, 1999.
38. Remy, I., Wilson, I. A., and Michnick, S. W. Erythropoietin receptor activation by a ligand-induced conformation change. Science (Wash.
DC), 283: 990 –993, 1999.
39. Duhe, R. J., and Farrar, W. L. Characterization of active and
inactive forms of the JAK2 protein- tyrosine kinase produced via the
baculovirus expression vector system. J. Biol. Chem., 270: 23084 –
23089, 1995.
40. Zhou, Y. J., Hanson, E. P., Chen, Y. Q., Magnuson, K., Chen, M.,
Swann, P. G., Wange, R. L., Changelian, P. S., and O’Shea, J. J. Distinct
tyrosine phosphorylation sites in JAK3 kinase domain positively and
negatively regulate its enzymatic activity, Proc. Natl. Acad. Sci. USA
94: 13850 –13855., 1997.
41. Notarangelo, L. D. Immunodeficiencies caused by genetic defects
in protein kinases. Curr. Opin. Immunol., 8: 448 – 453, 1996.
42. Lacronique, V., Boureux, A., Valle, V. D., Poirel, H., Quang, C. T.,
Mauchauffe, M., Berthou, C., Lessard, M., Berger, R., Ghysdael, J., and
Bernard, O. A. A TEL-JAK2 fusion protein with constitutive kinase
activity in human leukemia. Science (Wash. DC), 278: 1309 –1312,
1997.
43. Peeters, P., Raynaud, S. D., Cools, J., Wlodarska, I., Grosgeorge, J.,
Philip, P., Monpoux, F., Van Rompaey, L., Baens, M., Van den Berghe,
H., and Marynen, P. Fusion of TEL, the ETS-variant gene 6 (ETV6), to
the receptor- associated kinase JAK2 as a result of t(9;12) in a lymphoid
and t(9;15;12) in a myeloid leukemia. Blood, 90: 2535–2540, 1997.
44. Migone, T. S., Lin, J. X., Cereseto, A., Mulloy, J. C., O’Shea, J. J.,
Franchini, G., and Leonard, W. J. Constitutively activated Jak-STAT
pathway in T cells transformed with HTLV-I. Science (Wash. DC), 269:
79 – 81, 1995.
45. Danial, N. N., Pernis, A., and Rothman, P. B. Jak-STAT signaling
induced by the v-abl oncogene. Science (Wash. DC), 269: 1875–1877,
1995.
46. Darnell, J. E., Jr. STATs and gene regulation, Science (Wash. DC),
277: 1630 –1635, 1997.
47. Fu, X. Y., Schindler, C., Improta, T., Aebersold, R., and Darnell,
J. E., Jr. The proteins of ISGF-3, the interferon ␣-induced transcriptional
activator, define a gene family involved in signal transduction, Proc.
Natl. Acad. Sci. USA, 89: 7840 –7843, 1992.
48. Khan, K. D., Shuai, K., Lindwall, G., Maher, S. E., Darnell, J. E.,
Jr., and Bothwell, A. L. Induction of the Ly-6A/E gene by interferon ␣/␤
and ␥ requires a DNA element to which a tyrosine-phosphorylated
91-kDa protein binds, Proc. Natl. Acad. Sci. USA, 90: 6806 – 6810,
1993.
49. Shuai, K., Schindler, C., Prezioso, V. R., and Darnell, J. E., Jr.
Activation of transcription by IFN-␥: tyrosine phosphorylation of a
91-kD DNA binding protein, Science (Wash. DC), 258: 1808 –1812,
1992.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
544 Cellular Signaling Pathways as Therapeutic Targets
50. Shuai, K., Stark, G. R., Kerr, I. M., and Darnell, J. E., Jr. A single
phosphotyrosine residue of Stat91 required for gene activation by interferon-␥. Science (Wash. DC), 261: 1744 –1746, 1993.
51. Zhong, Z., Wen, Z., and Darnell, J. E., Jr. Stat3: a STAT family
member activated by tyrosine phosphorylation in response to epidermal
growth factor and interleukin-6. Science (Wash. DC), 264: 95–98, 1994.
52. Shuai, K., Horvath, C. M., Huang, L. H., Qureshi, S. A., Cowburn,
D., and Darnell, J. E., Jr. Interferon activation of the transcription factor
Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell, 76: 821– 828, 1994.
53. Kohlhuber, F., Rogers, N. C., Watling, D., Feng, J., Guschin, D.,
Briscoe, J., Witthuhn, B. A., Kotenko, S. V., Pestka, S., Stark, G. R.,
Ihle, J. N., and Kerr, I. M. A JAK1/JAK2 chimera can sustain ␣ and ␥
interferon responses. Mol. Cell. Biol., 17: 695–706, 1997.
54. Kotenko, S. V., Izotova, L. S., Pollack, B. P., Muthukumaran, G.,
Paukku, K., Silvennoinen, O., Ihle, J. N., and Pestka, S. Other kinases
can substitute for Jak2 in signal transduction by interferon-␥. J. Biol.
Chem., 271: 17174 –17182, 1996.
55. Bhattacharya, S., Eckner, R., Grossman, S., Oldread, E., Arany, Z.,
D’Andrea, A., and Livingston, D. M. Cooperation of Stat2 and p300/
CBP in signalling induced by interferon- ␣. Nature (Lond.), 383: 344 –
347, 1996.
56. Horvai, A. E., Xu, L., Korzus, E., Brard, G., Kalafus, D., Mullen,
T. M., Rose, D. W., Rosenfeld, M. G., and Glass, C. K. Nuclear
integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300.
Proc. Natl. Acad. Sci. USA, 94: 1074 –1079, 1997.
57. Eilers, A., Georgellis, D., Klose, B., Schindler, C., Ziemiecki, A.,
and Harpur, A. G. Differentiation-regulated serine phosphorylation of
STAT1 promotes GAF activation in macrophages. Mol. Cell. Biol., 15:
3579 –3586, 1995.
58. Schindler, C. STATs as activators of apoptosis. Trends Cell Biol.,
8: 97–98, 1998.
59. Mui, A. L. The role of STATs in proliferation, differentiation, and
apoptosis. Cell Mol. Life Sci., 55: 1547–1458, 1999.
60. Chin, Y. E., Kitagawa, M., Su, W. C., You, Z. H., Iwamoto, Y., and
Fu, X. Y. Cell growth arrest and induction of cyclin-dependent kinase
inhibitor p21 WAF1/CIP1 mediated by STAT1. Science (Wash. DC),
272: 719 –722, 1996.
61. Mui, A. L., Wakao, H., Kinoshita, T., Kitamura, T., and Miyajima,
A. Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J., 15: 2425–
2433, 1996.
62. O’Farrell, A. M., Liu, Y., Moore, K. W., and Mui, A. L. IL-10
inhibits macrophage activation and proliferation by distinct signaling
mechanisms: evidence for Stat3-dependent and -independent pathways.
EMBO J., 17: 1006 –1018, 1998.
63. Chaturvedi, P., Reddy, M. V., and Reddy, E. P. Src kinases and not
JAKs activate STATs during IL-3 induced myeloid cell proliferation.
Oncogene, 16: 1749 –1758, 1998.
64. Kumar, A., Commane, M., Flickinger, T. W., Horvath, C. M., and
Stark, G. R. Defective TNF-␣-induced apoptosis in STAT1-null cells
due to low constitutive levels of caspases. Science (Wash. DC), 278:
1630 –1632, 1997.
65. Zamorano, J., and Keegan, A. D. Regulation of apoptosis by
tyrosine-containing domains of IL-4R ␣: Y497 and Y713, but not the
STAT6-docking tyrosines, signal protection from apoptosis. J. Immunol., 161: 859 – 867, 1998.
66. Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani,
Y., Yamaguchi, T., Nakajima, K., and Hirano, T. Two signals are necessary
for cell proliferation induced by a cytokine receptor gp130: involvement of
STAT3 in anti-apoptosis. Immunity, 5: 449 – 460, 1996.
67. Xu, X., Fu, X. Y., Plate, J., and Chong, A. S. IFN-␥ induces cell
growth inhibition by Fas-mediated apoptosis: requirement of STAT1
protein for up-regulation of Fas and FasL expression. Cancer Res., 58:
2832–2837, 1998.
68. Kim, T. K., and Maniatis, T. Regulation of interferon-␥-activated
STAT1 by the ubiquitin- proteasome pathway. Science (Wash. DC),
273: 1717–1719, 1996.
69. An, W. G., Hwang, S. G., Trepel, J. B., and Blagosklonny, M. V.
Protease inhibitor-induced apoptosis: accumulation of wt p53,
p21WAF1/CIP1, and induction of apoptosis are independent markers of
proteasome inhibition. Leukemia (Baltimore), 14: 1276 –1283, 2000.
70. Starr, R., and Hilton, D. J. Negative regulation of the Jak/Stat
pathway. Bioassays, 21: 47–52, 1999.
71. Hilton, D. J. Negative regulators of cytokine signal transduction.
Cell Mol. Life Sci., 55: 1568 –1577, 1999.
72. Jiao, H., Yang, W., Berrada, K., Tabrizi, M., Shultz, L., and Yi, T.
Macrophages from motheaten and viable motheaten mutant mice show
increased proliferative responses to GM-CSF: detection of potential
HCP substrates in GM-CSF signal transduction. Exp. Hematol., 25:
592– 600, 1997.
73. Alexander, W. S., Starr, R., Metcalf, D., Nicholson, S. E., Farley,
A., Elefanty, A. G., Brysha, M., Kile, B. T., Richardson, R., Baca, M.,
Zhang, J. G., Willson, T. A., Viney, E. M., Sprigg, N. S., Rakar, S.,
Corbin, J., Mifsud, S., DiRago, L., Cary, D., Nicola, N. A., and Hilton,
D. J. Suppressors of cytokine signaling (SOCS): negative regulators of
signal transduction. J. Leukoc. Biol., 66: 588 –592, 1999.
74. Nicholson, S. E., Willson, T. A., Farley, A., Starr, R., Zhang, J. G.,
Baca, M., Alexander, W. S., Metcalf, D., Hilton, D. J., and Nicola, N. A.
Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal
transduction. EMBO J., 18: 375–385, 1999.
75. Adams, T. E., Hansen, J. A., Starr, R., Nicola, N. A., Hilton, D. J.,
and Billestrup, N. Growth hormone preferentially induces the rapid,
transient expression of SOCS-3, a novel inhibitor of cytokine receptor
signaling. J. Biol. Chem., 273: 1285–1287, 1998.
76. Song, M. M., and Shuai, K. The suppressor of cytokine signaling
(SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J. Biol. Chem., 273:
35056 –35062, 1998.
77. Schultheis, B., Carapeti-Marootian, M., Hochhaus, A., Weisser, A.,
Goldman, J. M., and Melo, J. V. Overexpression of SOCS-2 in advanced
stages of chronic myeloid leukemia: possible inadequacy of a negative
feedback mechanism. Blood, 99: 1766 –1775, 2002.
78. Porter, A. C., and Vaillancourt, R. R. Tyrosine kinase receptoractivated signal transduction pathways which lead to oncogenesis. Oncogene, 17: 1343–1352, 1998.
79. Drexler, H. G. Expression of FLT3 receptor and response to FLT3
ligand by leukemic cells. Leukemia (Baltimore), 10: 588 –599, 1996.
80. Blume-Jensen, P., and Hunter, T. Oncogenic kinase signalling.
Nature (Lond.), 411: 355–365, 2001.
81. Weiss, F. U., Daub, H., and Ullrich, A. Novel mechanisms of RTK
signal generation. Curr. Opin. Genet. Dev., 7: 80 – 86, 1997.
82. Weiss, A., and Schlessinger, J. Switching signals on or off by
receptor dimerization. Cell, 94: 277–280, 1998.
83. Sherr, C. J. Colony-stimulating factor-1 receptor. Blood, 75: 1–12,
1990.
84. Matthews, W., Jordan, C. T., Wiegand, G. W., Pardoll, D., and
Lemischka, I. R. A receptor tyrosine kinase specific to hematopoietic
stem and progenitor cell-enriched populations. Cell, 65: 1143–1152,
1991.
85. Tse, K. F., Mukherjee, G., and Small, D. Constitutive activation of
FLT3 stimulates multiple intracellular signal transducers and results in
transformation. Leukemia (Baltimore), 14: 1766 –1776, 2000.
86. Gilliland, D. G., and Griffin, J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood, 100: 1532–1542, 2002.
87. Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schakel, U.,
Platzbecker, U., Wermke, M., Bornhauser, M., Ritter, M., Neubauer,
A., Ehninger, G., and Illmer, T. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association
with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99: 4326 – 4335, 2002.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 545
88. Gilliland, D. G., and Griffin, J. D. Role of FLT3 in leukemia. Curr.
Opin. Hematol., 9: 274 –281, 2002.
89. Kiyoi, H., Ohno, R., Ueda, R., Saito, H., and Naoe, T. Mechanism
of constitutive activation of FLT3 with internal tandem duplication in
the juxtamembrane domain. Oncogene, 21: 2555–2563, 2002.
90. Kelly, L. M., Liu, Q., Kutok, J. L., Williams, I. R., Boulton, C. L.,
and Gilliland, D. G. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative
disease in a murine bone marrow transplant model. Blood, 99: 310 –318,
2002.
91. Yamamoto, Y., Kiyoi, H., Nakano, Y., Suzuki, R., Kodera, Y.,
Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C.,
Akiyama, H., Saito, K., Nishimura, M., Motoji, T., Shinagawa, K.,
Takeshita, A., Saito, H., Ueda, R., Ohno, R., and Naoe, T. Activating
mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood, 97: 2434 –2439, 2001.
92. Levis, M., Tse, K. F., Smith, B. D., Garrett, E., and Small, D. A
FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid
leukemia blasts harboring FLT3 internal tandem duplication mutations.
Blood, 98: 885– 887, 2001.
93. Levis, M., Allebach, J., Tse, K. F., Zheng, R., Baldwin, B. R.,
Smith, B. D., Jones-Bolin, S., Ruggeri, B., Dionne, C., and Small, D. A
FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in
vitro and in vivo. Blood, 99: 3885–3891, 2002.
94. Schwartzberg, P. L. The many faces of Src: multiple functions of a
prototypical tyrosine kinase. Oncogene, 17: 1463–1468, 1998.
95. Lee, J. T., Jr., and McCubrey, J. A. The Raf/MEK/ERK signal
transduction cascade as a target for chemotherapeutic intervention in
leukemia. Leukemia (Baltimore), 16: 486 –507, 2002.
96. Beaupre, D. M., and Kurzrock, R. RAS and leukemia: from basic
mechanisms to gene-directed therapy. J. Clin. Oncol., 17: 1071–1079,
1999.
97. Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J., and
Der, C. J. Increasing complexity of Ras signaling. Oncogene, 17:
1395–1413, 1998.
98. Prendergast, G. C., and Gibbs, J. B. Ras regulatory interactions:
novel targets for anti-cancer intervention? Bioessays, 16: 187–191,
1994.
99. Crews, C. M., and Erikson, R. L. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell, 74: 215–217,
1993.
100. Crews, C. M., Alessandrini, A., and Erikson, R. L. Erks: their
fifteen minutes has arrived. Cell Growth Differ., 3: 135–142, 1992.
101. Dhanasekaran, N., and Premkumar Reddy, E. Signaling by dual
specificity kinases. Oncogene, 17: 1447–1455, 1998.
102. Marais, R., Wynne, J., and Treisman, R. The SRF accessory
protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell, 73: 381–393, 1993.
103. Boulton, T. G., Nye, S. H., Robbins, D. J., Ip, N. Y., Radziejewska, E., Morgenbesser, S. D., DePinho, R. A., Panayotatos, N., Cobb,
M. H., and Yancopoulos, G. D. ERKs: a family of protein-serine/
threonine kinases that are activated and tyrosine phosphorylated in
response to insulin and NGF. Cell, 65: 663– 675, 1991.
104. Nebreda, A. R., and Gavin, A. C. Perspectives: signal transduction. Cell survival demands some Rsk. Science (Wash. DC), 286:
1309 –1310, 1999.
105. Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A.,
and Greenberg, M. E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science (Wash. DC), 286: 1358 –1362, 1999.
106. Kerkhoff, E., and Rapp, U. R. Cell cycle targets of Ras/Raf
signalling. Oncogene, 17: 1457–1462, 1998.
107. Sherr, C. J. Growth factor-regulated G1 cyclins. Stem Cells, 12:
47–57, 1994.
108. Mayol, X., and Grana, X. pRB, p107 and p130 as transcriptional
regulators: role in cell growth and differentiation. Prog. Cell Cycle Res.,
3: 157–169, 1997.
109. Dimri, G. P., Nakanishi, M., Desprez, P. Y., Smith, J. R., and
Campisi, J. Inhibition of E2F activity by the cyclin-dependent protein
kinase inhibitor p21 in cells expressing or lacking a functional retinoblastoma protein. Mol. Cell. Biol., 16: 2987–2997, 1996.
110. Steinman, R. A. Cell cycle regulators and hematopoiesis. Oncogene, 21: 3403–3413, 2002.
111. Jiang, Y., Gram, H., Zhao, M., New, L., Gu, J., Feng, L., Di
Padova, F., Ulevitch, R. J., and Han, J. Characterization of the structure
and function of the fourth member of p38 group mitogen-activated
protein kinases, p38␦. J. Biol. Chem., 272: 30122–30128, 1997.
112. Lechner, C., Zahalka, M. A., Giot, J. F., Moller, N. P., and Ullrich,
A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc. Natl. Acad. Sci. USA, 93: 4355– 4359, 1996.
113. Enslen, H., Brancho, D. M., and Davis, R. J. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms.
EMBO J., 19: 1301–1311, 2000.
114. Uddin, S., Majchrzak, B., Woodson, J., Arunkumar, P., Alsayed,
Y., Pine, R., Young, P. R., Fish, E. N., and Platanias, L. C. Activation
of the p38 mitogen-activated protein kinase by type I interferons. J. Biol.
Chem., 274: 30127–30131, 1999.
115. Mayer, I. A., Verma, A., Grumbach, I. M., Uddin, S., Lekmine, F.,
Ravandi, F., Majchrzak, B., Fujita, S., Fish, E. N., and Platanias, L. C.
The p38 MAPK pathway mediates the growth inhibitory effects of
interferon-␣ in BCR-ABL-expressing cells. J. Biol. Chem., 276:
28570 –28577, 2001.
116. Verma, A., Deb, D. K., Sassano, A., Uddin, S., Varga, J., Wickrema, A., and Platanias, L. C. Activation of the p38 mitogen-activated
protein kinase mediates the suppressive effects of type I interferons and
transforming growth factor-␤ on normal eematopoiesis. J. Biol. Chem.,
277: 7726 –7735, 2002.
117. Ichijo, H. From receptors to stress-activated MAP kinases. Oncogene, 18: 6087– 6093, 1999.
118. Fuchs, S. Y., Adler, V., Pincus, M. R., and Ronai, Z. MEKK1/JNK
signaling stabilizes and activates p53. Proc. Natl. Acad. Sci. USA, 95:
10541–10546, 1998.
119. Keyse, S. M. Protein phosphatases and the regulation of mitogenactivated protein kinase signalling. Curr. Opin. Cell Biol., 12: 186 –192,
2000.
120. Camps, M., Nichols, A., Gillieron, C., Antonsson, B., Muda, M.,
Chabert, C., Boschert, U., and Arkinstall, S. Catalytic activation of the
phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science (Wash. DC), 280: 1262–1265, 1998.
121. Camps, M., Nichols, A., and Arkinstall, S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J.,
14: 6 –16, 2000.
122. Chung, H., and Brautigan, D. L. Protein phosphatase 2A suppresses MAP kinase signalling and ectopic protein expression. Cell
Signalling, 11: 575–580, 1999.
123. Wassarman, D. A., Solomon, N. M., Chang, H. C., Karim, F. D.,
Therrien, M., and Rubin, G. M. Protein phosphatase 2A positively and
negatively regulates Ras1- mediated photoreceptor development in Drosophila. Genes Dev., 10: 272–278, 1996.
124. Klippel, A., Escobedo, J. A., Fantl, W. J., and Williams, L. T. The
C-terminal SH2 domain of p85 accounts for the high affinity and
specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor ␤ receptor. Mol. Cell. Biol., 12:
1451–1459, 1992.
125. Hiles, I. D., Otsu, M., Volinia, S., Fry, M. J., Gout, I., Dhand, R.,
Panayotou, G., Ruiz-Larrea, F., Thompson, A., Totty, N. F., et al.
Phosphatidylinositol 3-kinase: structure and expression of the 110 kd
catalytic subunit. Cell, 70: 419 – 429, 1992.
126. Shoelson, S. E., Sivaraja, M., Williams, K. P., Hu, P., Schlessinger, J.,
and Weiss, M. A. Specific phosphopeptide binding regulates a conformational change in the PI 3-kinase SH2 domain associated with enzyme
activation. EMBO J., 12: 795– 802, 1993.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
546 Cellular Signaling Pathways as Therapeutic Targets
127. Anderson, K. E., Coadwell, J., Stephens, L. R., and Hawkins, P. T.
Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr. Biol., 8: 684 – 691, 1998.
128. Scheid, M. P., and Duronio, V. Dissociation of cytokine-induced
phosphorylation of Bad and activation of PKB/akt: involvement of
MEK upstream of Bad phosphorylation. Proc. Natl. Acad. Sci. USA, 95:
7439 –7444, 1998.
129. del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R., and
Nunez, G. Interleukin-3-induced phosphorylation of BAD through the
protein kinase Akt. Science (Wash. DC), 278: 687– 689, 1997.
130. Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y.,
and Greenberg, M. E. Akt phosphorylation of BAD couples survival
signals to the cell- intrinsic death machinery. Cell, 91: 231–241, 1997.
131. Khwaja, A. Akt is more than just a Bad kinase. Nature (Lond.),
401: 33–34, 1999.
132. Dong, F., and Larner, A. C. Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a
tyrosine kinase activity distinct from the Janus kinases. Blood, 95:
1656 –1662, 2000.
133. Aoki, M., Batista, O., Bellacosa, A., Tsichlis, P., and Vogt, P. K.
The akt kinase: molecular determinants of oncogenicity. Proc. Natl.
Acad. Sci. USA, 95: 14950 –14955, 1998.
134. Sellers, W. R., and Fisher, D. E. Apoptosis and cancer drug
targeting. J. Clin. Investig., 104: 1655–1661, 1999.
135. Blagosklonny, M. V., Chuman, Y., Bergan, R. C., and Fojo, T.
Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in
leukemia cells. Leukemia (Baltimore), 13: 1028 –1036, 1999.
136. Pahl, H. L. Activators and target genes of Rel/NF-␬B transcription
factors. Oncogene, 18: 6853– 6866, 1999.
137. Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I.,
Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S. H.,
Giovanella, B. C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler,
M. H., and Parsons, R. PTEN, a putative protein tyrosine phosphatase
gene mutated in human brain, breast, and prostate cancer. Science
(Wash. DC), 275: 1943–1947, 1997.
138. Stambolic, V., Suzuki, A., de la Pompa, J. L., Brothers, G. M.,
Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J. M., Siderovski, D. P.,
and Mak, T. W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95: 29 –39, 1998.
139. Maehama, T., and Dixon, J. E. The tumor suppressor. PTEN/
MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J. Biol. Chem., 273: 13375–13378, 1998.
140. Myers, M. P., Pass, I., Batty, I. H., Van der Kaay, J., Stolarov,
J. P., Hemmings, B. A., Wigler, M. H., Downes, C. P., and Tonks, N. K.
The lipid phosphatase activity of PTEN is critical for its tumor supressor
function. Proc. Natl. Acad. Sci. USA, 95: 13513–13518, 1998.
141. Podsypanina, K., Ellenson, L. H., Nemes, A., Gu, J., Tamura, M.,
Yamada, K. M., Cordon-Cardo, C., Catoretti, G., Fisher, P. E., and
Parsons, R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA, 96: 1563–1568, 1999.
142. Hu, Z. B., Minden, M. D., and McCulloch, E. A. Phosphorylation
of BCL-2 after exposure of human leukemic cells to retinoic acid.
Blood, 92: 1768 –1775, 1998.
143. Haldar, S., Basu, A., and Croce, C. M. Bcl2 is the guardian of
microtubule integrity. Cancer Res., 57: 229 –233, 1997.
144. Asaoka, Y., Nakamura, S., Yoshida, K., and Nishizuka, Y. Protein
kinase C, calcium and phospholipid degradation. Trends Biochem. Sci.,
17: 414 – 417, 1992.
145. Liou, H. C., and Baltimore, D. Regulation of the NF-␬ B/rel
transcription factor and I ␬ B inhibitor system. Curr. Opin. Cell Biol., 5:
477– 487, 1993.
146. Nishizuka, Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science (Wash. DC), 258:
607– 614, 1992.
147. Kovanen, P. E., Junttila, I., Takaluoma, K., Saharinen, P., Valmu,
L., Li, W., and Silvennoinen, O. Regulation of Jak2 tyrosine kinase by
protein kinase C during macrophage differentiation of IL-3-dependent
myeloid progenitor cells. Blood, 95: 1626 –1632, 2000.
148. Kolch, W., Heidecker, G., Kochs, G., Hummel, R., Vahidi, H.,
Mischak, H., Finkenzeller, G., Marme, D., and Rapp, U. R. Protein
kinase C ␣ activates RAF-1 by direct phosphorylation. Nature (Lond.),
364: 249 –252, 1993.
149. Seynaeve, C. M., Kazanietz, M. G., Blumberg, P. M., Sausville,
E. A., and Worland, P. J. Differential inhibition of protein kinase C
isozymes by UCN-01, a staurosporine analogue. Mol. Pharmacol., 45:
1207–1214, 1994.
150. Thavasu, P., Propper, D., McDonald, A., Dobbs, N., Ganesan, T.,
Talbot, D., Braybrook, J., Caponigro, F., Hutchison, C., Twelves, C.,
Man, A., Fabbro, D., Harris, A., and Balkwill, F. The protein kinase C
inhibitor CGP41251 suppresses cytokine release and extracellular
signal-regulated kinase 2 expression in cancer patients. Cancer Res., 59:
3980 –3984, 1999.
151. King, W. G., Mattaliano, M. D., Chan, T. O., Tsichlis, P. N., and
Brugge, J. S. Phosphatidylinositol 3-kinase is required for integrinstimulated AKT and Raf-1/mitogen-activated protein kinase pathway
activation. Mol. Cell. Biol., 17: 4406 – 4418, 1997.
152. Wennstrom, S., and Downward, J. Role of phosphoinositide 3kinase in activation of ras and mitogen- activated protein kinase by
epidermal growth factor. Mol. Cell. Biol., 19: 4279 – 4288, 1999.
153. McCubrey, J. A., Lee, J. T., Steelman, L. S., Blalock, W. L.,
Moye, P. W., Chang, F., Pearce, M., Shelton, J. G., White, M. K.,
Franklin, R. A., and Pohnert, S. C. Interactions between the PI3K and
Raf signaling pathways can result in the transformation of hematopoietic
cells. Cancer Detect. Prev., 25: 375–393, 2001.
154. Platanias, L. C., and Fish, E. N. Signaling pathways activated by
interferons. Exp. Hematol., 27: 1583–1592, 1999.
155. David, M., Petricoin, E., 3rd, Benjamin, C., Pine, R., Weber, M. J.,
and Larner, A. C. Requirement for MAP kinase (ERK2) activity in
interferon ␣- and interferon ␤-stimulated gene expression through
STAT proteins. Science (Wash. DC), 269: 1721–1723, 1995.
156. Dickens, M., Rogers, J. S., Cavanagh, J., Raitano, A., Xia, Z.,
Halpern, J. R., Greenberg, M. E., Sawyers, C. L., and Davis, R. J. A
cytoplasmic inhibitor of the JNK signal transduction pathway. Science
(Wash. DC), 277: 693– 696, 1997.
157. Sawyers, C. L., McLaughlin, J., and Witte, O. N. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells
by the Bcr-Abl oncogene. J. Exp. Med., 181: 307–313, 1995.
158. Skorski, T., Kanakaraj, P., Nieborowska-Skorska, M., Ratajczak,
M. Z., Wen, S. C., Zon, G., Gewirtz, A. M., Perussia, B., and Calabretta,
B. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and
is required for the growth of Philadelphia chromosome-positive cells.
Blood, 86: 726 –736, 1995.
159. Oda, T., Heaney, C., Hagopian, J. R., Okuda, K., Griffin, J. D., and
Druker, B. J. Crkl is the major tyrosine-phosphorylated protein in
neutrophils from patients with chronic myelogenous leukemia. J. Biol.
Chem., 269: 22925–22928, 1994.
160. Ilaria, R. L., Jr., and Van Etten, R. A. P210 and P190(BCR/ABL)
induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J. Biol. Chem., 271: 31704 –
31710, 1996.
161. Pendergast, A. M., Quilliam, L. A., Cripe, L. D., Bassing, C. H.,
Dai, Z., Li, N., Batzer, A., Rabun, K. M., Der, C. J., Schlessinger, J., et
al. BCR-ABL-induced oncogenesis is mediated by direct interaction
with the SH2 domain of the GRB-2 adaptor protein. Cell, 75: 175–185,
1993.
162. Tauchi, T., Miyazawa, K., Feng, G. S., Broxmeyer, H. E., and
Toyama, K. A coiled-coil tetramerization domain of BCR-ABL is
essential for the interactions of SH2-containing signal transduction
molecules. J. Biol. Chem., 272: 1389 –1394, 1997.
163. Salgia, R., Sattler, M., Pisick, E., Li, J. L., and Griffin, J. D.
p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl. Exp. Hematol.,
24: 310 –313, 1996.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 547
164. Levitzki, A., and Gazit, A. Tyrosine kinase inhibition: an approach
to drug development. Science (Wash. DC), 267: 1782–1788, 1995.
165. Levitzki, A. Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and directors of signal transduction. FASEB J., 6:
3275–3282, 1992.
166. Sawyers, C. L., and Druker, B. Tyrosine kinase inhibitors in
chronic myeloid leukemia. Cancer J. Sci. Am., 5: 63– 69, 1998.
167. Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E.,
Ford, J. M., Lydon, N. B., Kantarjian, H., Capdeville, R., Ohno-Jones,
S., and Sawyers, C. L. Efficacy and safety of a specific inhibitor of the
BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl.
J. Med., 344: 1031–1037, 2001.
168. Druker, B. J., Sawyers, C. L., Kantarjian, H., Resta, D. J., Reese,
S. F., Ford, J. M., Capdeville, R., and Talpaz, M. Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med., 344: 1038 –1042, 2001.
169. Kantarjian, H., Sawyers, C., Hochhaus, A., Guilhot, F., Schiffer,
C., Gambacorti-Passerini, C., Niederwieser, D., Resta, D., Capdeville,
R., Zoellner, U., Talpaz, M., and Druker, B. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.
N. Engl. J. Med., 346: 645– 652, 2002.
170. Talpaz, M., Silver, R. T., Druker, B. J., Goldman, J. M., GambacortiPasserini, C., Guilhot, F., Schiffer, C. A., Fischer, T., Deininger, M. W.,
Lennard, A. L., Hochhaus, A., Ottmann, O. G., Gratwohl, A., Baccarani,
M., Stone, R., Tura, S., Mahon, F. X., Fernandes-Reese, S., Gathmann, I.,
Capdeville, R., Kantarjian, H. M., and Sawyers, C. L. Imatinib induces
durable hematologic and cytogenetic responses in patients with accelerated
phase chronic myeloid leukemia: results of a phase 2 study. Blood, 99:
1928 –1937, 2002.
171. Dierov, J., Xu, Q., Dierova, R., and Carroll, M. TEL/plateletderived growth factor receptor ␤ activates phosphatidylinositol 3 (PI3)
kinase and requires PI3 kinase to regulate the cell cycle. Blood, 99:
1758 –1765, 2002.
172. Golub, T. R., Barker, G. F., Lovett, M., and Gilliland, D. G. Fusion
of PDGF receptor ␤ to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell, 77: 307–
316, 1994.
173. Magnusson, M. K., Meade, K. E., Brown, K. E., Arthur, D. C.,
Krueger, L. A., Barrett, A. J., and Dunbar, C. E. Rabaptin-5 is a novel
fusion partner to platelet-derived growth factor ␤ receptor in chronic
myelomonocytic leukemia. Blood, 98: 2518 –2525, 2001.
174. Magnusson, M. K., Meade, K. E., Nakamura, R., Barrett, J., and
Dunbar, C. E. Activity of STI571 in chronic myelomonocytic leukemia
with a platelet- derived growth factor ␤ receptor fusion oncogene.
Blood, 100: 1088 –1091, 2002.
175. Mason, D. Y., Bastard, C., Rimokh, R., Dastugue, N., Huret, J. L.,
Kristoffersson, U., Magaud, J. P., Nezelof, C., Tilly, H., Vannier, J. P.,
et al. CD30-positive large cell lymphomas (’Ki-1 lymphoma’) are
associated with a chromosomal translocation involving 5q35, Br. J.
Haematol., 74: 161–168, 1990.
176. Wellmann, A., Otsuki, T., Vogelbruch, M., Clark, H. M., Jaffe,
E. S., and Raffeld, M. Analysis of the t(2;5)(p23;q35) translocation by
reverse transcription- polymerase chain reaction in CD30⫹ anaplastic
large-cell lymphomas, in other non-Hodgkin’s lymphomas of T-cell
phenotype, and in Hodgkin’s disease. Blood, 86: 2321–2328, 1995.
177. Bischof, D., Pulford, K., Mason, D. Y., and Morris, S. W. Role of
the nucleophosmin (NPM) portion of the non-Hodgkin’s lymphomaassociated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol. Cell. Biol., 17: 2312–3325, 1997.
178. Fujimoto, J., Shiota, M., Iwahara, T., Seki, N., Satoh, H., Mori, S.,
and Yamamoto, T. Characterization of the transforming activity of p80,
a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc. Natl. Acad. Sci. USA, 93: 4181–
4186, 1996.
179. Bai, R. Y., Dieter, P., Peschel, C., Morris, S. W., and Duyster,
J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic
lymphoma is a constitutively active tyrosine kinase that utilizes phos-
pholipase C-␥ to mediate its mitogenicity. Mol. Cell. Biol., 18: 6951–
6961, 1998.
180. Bai, R. Y., Ouyang, T., Miething, C., Morris, S. W., Peschel, C.,
and Duyster, J. Nucleophosmin-anaplastic lymphoma kinase associated
with anaplastic large-cell lymphoma activates the phosphatidylinositol
3-kinase/Akt antiapoptotic signaling pathway. Blood, 96: 4319 – 4327,
2000.
181. Nieborowska-Skorska, M., Slupianek, A., Xue, L., Zhang, Q.,
Raghunath, P. N., Hoser, G., Wasik, M. A., Morris, S. W., and Skorski,
T. Role of signal transducer and activator of transcription 5 in nucleophosmin/anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. Cancer Res., 61: 6517– 6523, 2001.
182. Slupianek, A., Nieborowska-Skorska, M., Hoser, G., Morrione,
A., Majewski, M., Xue, L., Morris, S. W., Wasik, M. A., and Skorski,
T. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer
Res., 61: 2194 –2199, 2001.
183. Stein, H., Foss, H. D., Durkop, H., Marafioti, T., Delsol, G.,
Pulford, K., Pileri, S., and Falini, B. CD30(⫹) anaplastic large cell
lymphoma: a review of its histopathologic, genetic, and clinical features.
Blood, 96: 3681–3695, 2000.
184. Sachs, L. The control of hematopoiesis and leukemia: from basic
biology to the clinic. Proc. Natl. Acad. Sci. USA, 93: 4742– 4749, 1996.
185. Savino, R., Ciapponi, L., Lahm, A., Demartis, A., Cabibbo, A.,
Toniatti, C., Delmastro, P., Altamura, S., and Ciliberto, G. Rational
design of a receptor super-antagonist of human interleukin-6. EMBO J.,
13: 5863–5870, 1994.
186. Klein, B., Wijdenes, J., Zhang, X. G., Jourdan, M., Boiron, J. M.,
Brochier, J., Liautard, J., Merlin, M., Clement, C., Morel-Fournier, B.,
et al. Murine anti-interleukin-6 monoclonal antibody therapy for a
patient with plasma cell leukemia. Blood, 78: 1198 –1204, 1991.
187. Tse, K. F., Novelli, E., Civin, C. I., Bohmer, F. D., and Small, D.
Inhibition of FLT3-mediated transformation by use of a tyrosine kinase
inhibitor. Leukemia (Baltimore), 15: 1001–1010, 2001.
188. Kottaridis, P. D., Gale, R. E., Frew, M. E., Harrison, G., Langabeer, S. E., Belton, A. A., Walker, H., Wheatley, K., Bowen, D. T.,
Burnett, A. K., Goldstone, A. H., and Linch, D. C. The presence of a
FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk
group and response to the first cycle of chemotherapy: analysis of 854
patients from the United Kingdom Medical Research Council AML 10
and 12 trials. Blood, 98: 1752–1759, 2001.
189. Abu-Duhier, F. M., Goodeve, A. C., Wilson, G. A., Gari, M. A.,
Peake, I. R., Rees, D. C., Vandenberghe, E. A., Winship, P. R., and
Reilly, J. T. FLT3 internal tandem duplication mutations in adult acute
myeloid leukaemia define a high-risk group. Br. J. Haematol., 111:
190 –195, 2000.
190. Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E.,
Lapidot, Z., Leeder, J. S., Freedman, M., Cohen, A., Gazit, A., Levitzki,
A., and Roifman, C. M. Inhibition of acute lymphoblastic leukaemia by
a Jak-2 inhibitor. Nature (Lond.), 379: 645– 648, 1996.
191. Eriksen, K. W., Kaltoft, K., Mikkelsen, G., Nielsen, M., Zhang,
Q., Geisler, C., Nissen, M. H., Ropke, C., Wasik, M. A., and Odum, N.
Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490
inhibits STAT3-activation, interleukin-2 receptor expression and growth
of leukemic Sezary cells. Leukemia (Baltimore), 15: 787–793, 2001.
192. De Vos, J., Jourdan, M., Tarte, K., Jasmin, C., and Klein, B. JAK2
tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogenactivated protein kinase (MAPK) and signal transducer and activator of
transcription (STAT) pathways and induces apoptosis in myeloma cells.
Br. J. Haematol., 109: 823– 828, 2000.
193. Levitt, M. L., and Koty, P. P. Tyrosine kinase inhibitors in preclinical development. Investig. New Drugs, 17: 213–226, 1999.
194. Klohs, W. D., Fry, D. W., and Kraker, A. J. Inhibitors of tyrosine
kinase. Curr. Opin. Oncol., 9: 562–568, 1997.
195. Marra, F., Choudhury, G. G., and Abboud, H. E. Interferon-␥mediated activation of STAT1␣ regulates growth factor-induced mitogenesis. J. Clin. Investig., 98: 1218 –1230, 1996.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
548 Cellular Signaling Pathways as Therapeutic Targets
196. Turkson, J., Bowman, T., Garcia, R., Caldenhoven, E., De Groot,
R. P., and Jove, R. Stat3 activation by Src induces specific gene
regulation and is required for cell transformation. Mol. Cell. Biol., 18:
2545–2552, 1998.
197. Sillaber, C., Gesbert, F., Frank, D. A., Sattler, M., and Griffin,
J. D. STAT5 activation contributes to growth and viability in Bcr/Abltransformed cells. Blood, 95: 2118 –2125, 2000.
198. Frank, D. A., Mahajan, S., and Ritz, J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat.
Med., 5: 444 – 447, 1999.
199. Minucci, S., Nervi, C., Lo Coco, F., and Pelicci, P. G. Histone
deacetylases: a common molecular target for differentiation treatment of
acute myeloid leukemias? Oncogene, 20: 3110 –3115, 2001.
200. Amann, J. M., Nip, J., Strom, D. K., Lutterbach, B., Harada, H.,
Lenny, N., Downing, J. R., Meyers, S., and Hiebert, S. W. ETO, a target
of t(8;21) in acute leukemia, makes distinct contacts with multiple
histone deacetylases and binds mSin3A through its oligomerization
domain. Mol. Cell. Biol., 21: 6470 – 6483, 2001.
201. Guidez, F., and Zelent, A. Role of nuclear receptor corepressors in
leukemogenesis. Curr. Top. Microbiol. Immunol., 254: 165–185, 2001.
202. Chakrabarti, S. R., Sood, R., Nandi, S., and Nucifora, G. Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and
cell-cycle-dependent assembly into nuclear bodies. Proc. Natl. Acad.
Sci. USA, 97: 13281–13285, 2000.
203. Wang, J., Saunthararajah, Y., Redner, R. L., and Liu, J. M.
Inhibitors of histone deacetylase relieve ETO-mediated repression and
induce differentiation of AML1-ETO leukemia cells. Cancer Res., 59:
2766 –2769, 1999.
204. Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith,
A. B., Holland, J. C., Odchimar-Reissig, R., Stone, R. M., Nelson, D.,
Powell, B. L., DeCastro, C. M., Ellerton, J., Larson, R. A., Schiffer,
C. A., and Holland, J. F. Randomized controlled trial of azacitidine in
patients with the myelodysplastic syndrome: a study of the cancer and
leukemia group B. J. Clin. Oncol., 20: 2429 –2440, 2002.
205. Dyck, J. A., Maul, G. G., Miller, W. H., Jr., Chen, J. D., Kakizuka,
A., and Evans, R. M. A novel macromolecular structure is a target of the
promyelocyte- retinoic acid receptor oncoprotein. Cell, 76: 333–343,
1994.
206. Weis, K., Rambaud, S., Lavau, C., Jansen, J., Carvalho, T.,
Carmo-Fonseca, M., Lamond, A., and Dejean, A. Retinoic acid regulates aberrant nuclear localization of PML-RAR ␣ in acute promyelocytic leukemia cells. Cell, 76: 345–356, 1994.
207. Lin, R. J., Nagy, L., Inoue, S., Shao, W., Miller, W. H., Jr., and
Evans. R. M. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature (Lond.), 391: 811– 814, 1998.
208. Guidez, F., Ivins, S., Zhu, J., Soderstrom, M., Waxman, S., and
Zelent, A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RAR␣ underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood, 91:
2634 –2642, 1998.
209. Miller, W. H., Jr., and Waxman, S. Differentiation induction as a
treatment for hematologic malignancies, Oncogene, 21: 3496 –3506,
2002.
210. Jansen, J. H., de Ridder, M. C., Geertsma, W. M., Erpelinck, C. A.,
van Lom, K., Smit, E. M., Slater, R., vd Reijden, B. A., de Greef, G. E.,
Sonneveld, P., and Lowenberg, B. Complete remission of t(11;17)
positive acute promyelocytic leukemia induced by all-trans retinoic acid
and granulocyte colony-stimulating factor. Blood, 94: 39 – 45, 1999.
211. Gianni, M., Terao, M., Fortino, I., LiCalzi, M., Viggiano, V.,
Barbui, T., Rambaldi, A., and Garattini, E. Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells.
Blood, 89: 1001–1012, 1997.
212. Kolla, V., Weihua, X., and Kalvakolanu, D. V. Modulation of
interferon action by retinoids. Induction of murine STAT1 gene expression by retinoic acid (Published erratum appears in J. Biol. Chem., 272:
16068, 1997). J. Biol. Chem., 272: 9742–9748, 1997.
213. Matikainen, S., Ronni, T., Lehtonen, A., Sareneva, T., Melen, K.,
Nordling, S., Levy, D. E., and Julkunen, I. Retinoic acid induces signal
transducer and activator of transcription (STAT) 1. STAT2, and p48
expression in myeloid leukemia cells and enhances their responsiveness
to interferons. Cell Growth Differ., 8: 687– 698, 1997.
214. Miller, W. H., Jr., Schipper, H. M., Lee, J. S., Singer, J., and
Waxman, S. Mechanisms of action of arsenic trioxide. Cancer Res., 62:
3893–3903, 2002.
215. Chen, G. Q., Zhu, J., Shi, X. G., Ni, J. H., Zhong, H. J., Si, G. Y.,
Jin, X. L., Tang, W., Li, X. S., Xong, S. M., Shen, Z. X., Sun, G. L., Ma,
J., Zhang, P., Zhang, T. D., Gazin, C., Naoe, T., Chen, S. J., Wang,
Z. Y., and Chen, Z. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation
of Bcl-2 expression and modulation of PML-RAR ␣/PML proteins.
Blood, 88: 1052–1061, 1996.
216. Wang, Z. G., Rivi, R., Delva, L., Konig, A., Scheinberg, D. A.,
Gambacorti-Passerini, C., Gabrilove, J. L., Warrell, R. P., Jr., and
Pandolfi, P. P. Arsenic trioxide and melarsoprol induce programmed
cell death in myeloid leukemia cell lines and function in a PML and
PML-RAR␣ independent manner. Blood, 92: 1497–1504, 1998.
217. Shao, W., Fanelli, M., Ferrara, F. F., Riccioni, R., Rosenauer, A.,
Davison, K., Lamph, W. W., Waxman, S., Pelicci, P. G., Lo Coco, F.,
Avvisati, G., Testa, U., Peschle, C., Gambacorti-Passerini, C., Nervi, C.,
and Miller, W. H., Jr. Arsenic trioxide as an inducer of apoptosis and
loss of PML/RAR ␣ protein in acute promyelocytic leukemia cells.
J. Natl. Cancer Inst., 90: 124 –133, 1998.
218. Zhu, J., Koken, M. H., Quignon, F., Chelbi-Alix, M. K., Degos, L.,
Wang, Z. Y., Chen, Z., and de The, H. Arsenic-induced PML targeting
onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA, 94: 3978 –3983, 1997.
219. Coiffier, B., Lepage, E., Briere, J., Herbrecht, R., Tilly, H., Bouabdallah, R., Morel, P., Van Den Neste, E., Salles, G., Gaulard, P.,
Reyes, F., Lederlin, P., and Gisselbrecht, C. CHOP chemotherapy plus
rituximab compared with CHOP alone in elderly patients with diffuse
large-B-cell lymphoma. N. Engl. J. Med., 346: 235–242, 2002.
220. Rai, K. R. Future strategies toward the cure of indolent B-cell
malignancies. New biologic therapies. Semin. Hematol., 36: 12–17,
1999.
221. Keating, M. J. Chronic lymphocytic leukemia. Semin. Oncol., 26:
107–114, 1999.
222. Shan, D., Ledbetter, J. A., and Press, O. W. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies.
Blood, 91: 1644 –1652, 1998.
223. Byrd, J. C., Kitada, S., Flinn, I. W., Aron, J. L., Pearson, M.,
Lucas, D., and Reed, J. C. The mechanism of tumor cell clearance by
rituximab in vivo in patients with B-cell chronic lymphocytic leukemia:
evidence of caspase activation and apoptosis induction. Blood, 99:
1038 –1043, 2002.
224. Reed, J. C., Kitada, S., Kim, Y., and Byrd, J. Modulating apoptosis
pathways in low-grade B-cell malignancies using biological response
modifiers. Semin. Oncol., 29: 10 –24, 2002.
225. Adjei, A. A. Blocking oncogenic Ras signaling for cancer therapy.
J. Natl. Cancer Inst., 93: 1062–1074, 2001.
226. Kohl, N. E., Mosser, S. D., deSolms, S. J., Giuliani, E. A.,
Pompliano, D. L., Graham, S. L., Smith, R. L., Scolnick, E. M., Oliff,
A., and Gibbs, J. B. Selective inhibition of ras-dependent transformation
by a farnesyltransferase inhibitor. Science (Wash. DC), 260: 1934 –
1937, 1993.
227. James, G. L., Goldstein, J. L., Brown, M. S., Rawson, T. E.,
Somers, T. C., McDowell, R. S., Crowley, C. W., Lucas, B. K., Levinson, A. D., and Marsters, J. C., Jr. Benzodiazepine peptidomimetics:
potent inhibitors of Ras farnesylation in animal cells. Science (Wash.
DC), 260: 1937–1942, 1993.
228. Gibbs, J. B. Ras C-terminal processing enzymes–new drug targets? Cell, 65: 1– 4, 1991.
229. Karp, J. E., Lancet, J. E., Kaufmann, S. H., End, D. W., Wright,
J. J., Bol, K., Horak, I., Tidwell, M. L., Liesveld, J., Kottke, T. J., Ange,
D., Buddharaju, L., Gojo, I., Highsmith, W. E., Belly, R. T., Hohl, R. J.,
Rybak, M. E., Thibault, A., and Rosenblatt, J. Clinical and biologic
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Clinical Cancer Research 549
activity of the farnesyltransferase inhibitor R115777 in adults with
refractory and relapsed acute leukemias: a phase 1 clinical-laboratory
correlative trial. Blood, 97: 3361–3369, 2001.
230. Karp, J. E. Farnesyl protein transferase inhibitors as targeted
therapies for hematologic malignancies. Semin. Hematol., 38: 16 –23,
2001.
231. Adjei, A. A., Erlichman, C., Davis, J. N., Cutler, D. L., Sloan,
J. A., Marks, R. S., Hanson, L. J., Svingen, P. A., Atherton, P., Bishop,
W. R., Kirschmeier, P., and Kaufmann, S. H. A Phase I trial of the
farnesyl transferase inhibitor SCH66336: evidence for biological and
clinical activity. Cancer Res., 60: 1871–1877, 2000.
232. Kurzrock, R., Sebti, S. M., Kantarjian, H. M., Wright, J., Cortes,
J. E., Thomas, D. A., Wilson, E., Beran, M., Koller, C. A., O’Brien, S.,
Freireich, E. J., and Talpaz, M. Phase I Study of a Farnesyl Transferase
Inhibitor. R115777, in Patients with Myelodysplastic Syndrome. Blood,
98: 623a, 2001.
233. Blagosklonny, M. V., Fojo, T., Bhalla, K. N., Kim, J. S., Trepel,
J. B., Figg, W. D., Rivera, Y., and Neckers, L. M. The Hsp90 inhibitor
geldanamycin selectively sensitizes Bcr-Abl- expressing leukemia cells
to cytotoxic chemotherapy. Leukemia (Baltimore), 15: 1537–1543,
2001.
234. Soga, S., Neckers, L. M., Schulte, T. W., Shiotsu, Y., Akasaka, K.,
Narumi, H., Agatsuma, T., Ikuina, Y., Murakata, C., Tamaoki, T., and
Akinaga, S. KF25706, a novel oxime derivative of radicicol, exhibits in
vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res., 59: 2931–2938, 1999.
235. Shiotsu, Y., Neckers, L. M., Wortman, I., An, W. G., Schulte,
T. W., Soga, S., Murakata, C., Tamaoki, T., and Akinaga, S. Novel
oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90
complex. Blood, 96: 2284 –2291, 2000.
236. Propper, D. J., McDonald, A. C., Man, A., Thavasu, P., Balkwill,
F., Braybrooke, J. P., Caponigro, F., Graf, P., Dutreix, C., Blackie, R.,
Kaye, S. B., Ganesan, T. S., Talbot, D. C., Harris, A. L., and Twelves,
C. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein
kinase C. J. Clin. Oncol., 19: 1485–1492, 2001.
237. Okuda, K., Matulonis, U., Salgia, R., Kanakura, Y., Druker, B.,
and Griffin, J. D. Factor independence of human myeloid leukemia cell
lines is associated with increased phosphorylation of the proto-oncogene
Raf-1. Exp. Hematol., 22: 1111–1117, 1994.
238. Kang, C. D., Yoo, S. D., Hwang, B. W., Kim, K. W., Kim, D. W.,
Kim, C. M., Kim, S. H., and Chung, B. S. The inhibition of ERK/MAPK
not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leuk. Res., 24:
527–534, 2000.
239. Kim, S. C., Hahn, J. S., Min, Y. H., Yoo, N. C., Ko, Y. W., and
Lee, W. J. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK,
hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase. PAC1. Blood, 93: 3893–3899, 1999.
240. Morgan, M. A., Dolp, O., and Reuter, C. W. Cell-cycle-dependent
activation of mitogen-activated protein kinase kinase (MEK-1/2) in
myeloid leukemia cell lines and induction of growth inhibition and
apoptosis by inhibitors of RAS signaling. Blood, 97: 1823–1834, 2001.
241. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T., and Saltiel,
A. R. PD 098059 is a specific inhibitor of the activation of mitogenactivated protein kinase kinase in vitro and in vivo. J. Biol. Chem., 270:
27489 –27494, 1995.
242. Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel,
A. R. A synthetic inhibitor of the mitogen-activated protein kinase
cascade. Proc. Natl. Acad. Sci. USA, 92: 7686 –7689, 1995.
243. Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J.,
Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A.,
Hobbs, F., Copeland, R. A., Magolda, R. L., Scherle, P. A., and
Trzaskos, J. M. Identification of a novel inhibitor of mitogen-activated
protein kinase kinase. J. Biol. Chem., 273: 18623–18632, 1998.
244. Sebolt-Leopold, J. S. Development of anticancer drugs targeting
the MAP kinase pathway. Oncogene, 19: 6594 – 6599, 2000.
245. Powis, G., Bonjouklian, R., Berggren, M. M., Gallegos, A., Abraham,
R., Ashendel, C., Zalkow, L., Matter, W. F., Dodge, J., Grindey, G., et al.
Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3kinase. Cancer Res., 54: 2419 –2423, 1994.
246. Vlahos, C. J., Matter, W. F., Hui, K. Y., and Brown, R. F. A
specific inhibitor of phosphatidylinositol 3-kinase, 2-(4- morpholinyl)8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem., 269:
5241–5248, 1994.
247. Roth, W., and Reed, J. C. Apoptosis and cancer: when BAX is
TRAILing away. Nat. Med., 8: 216 –218, 2002.
248. Buolamwini, J. K. Novel anticancer drug discovery. Curr. Opin.
Chem. Biol., 3: 500 –509, 1999.
249. Martin, S. J. Destabilizing influences in apoptosis: sowing the
seeds of IAP destruction. Cell, 109: 793–796, 2002.
250. Stennicke, H. R., Ryan, C. A., and Salvesen, G. S. Reprieval from
execution: the molecular basis of caspase inhibition. Trends Biochem.
Sci., 27: 94 –101, 2002.
251. LaCasse, E. C., Baird, S., Korneluk, R. G., and MacKenzie, A. E.
The inhibitors of apoptosis (IAPs) and their emerging role in cancer.
Oncogene, 17: 3247–3259, 1998.
252. Holcik, M., Gibson, H., and Korneluk, R. G. XIAP: apoptotic
brake and promising therapeutic target. Apoptosis, 6: 253–261, 2001.
253. Tamm, I., Kornblau, S. M., Segall, H., Krajewski, S., Welsh, K.,
Kitada, S., Scudiero, D. A., Tudor, G., Qui, Y. H., Monks, A., Andreeff,
M., and Reed, J. C. Expression and prognostic significance of IAPfamily genes in human cancers and myeloid leukemias. Clin. Cancer
Res., 6: 1796 –1803, 2000.
254. Holcik, M., Yeh, C., Korneluk, R. G., and Chow, T. Translational
upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene, 19: 4174 – 4177, 2000.
255. Ciechanover, A. The ubiquitin-proteasome proteolytic pathway.
Cell, 79: 13–21, 1994.
256. Almond, J. B., and Cohen, G. M. The proteasome: a novel target
for cancer chemotherapy. Leukemia (Baltimore), 16: 433– 443, 2002.
257. King, R. W., Deshaies, R. J., Peters, J. M., and Kirschner, M. W.
How proteolysis drives the cell cycle. Science (Wash. DC), 274: 1652–
1659, 1996.
258. Karin, M., and Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-[␬]B activity. Annu. Rev. Immunol., 18: 621–
663, 2000.
259. Chang, Y. C., Lee, Y. S., Tejima, T., Tanaka, K., Omura, S.,
Heintz, N. H., Mitsui, Y., and Magae, J. mdm2 and bax, downstream
mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ., 9: 79 – 84, 1998.
260. Breitschopf, K., Zeiher, A. M., and Dimmeler, S. Ubiquitinmediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J. Biol. Chem., 275: 21648 –
21652, 2000.
261. Li, B., and Dou, Q. P. Bax degradation by the ubiquitin/proteasomedependent pathway: involvement in tumor survival and progression. Proc.
Natl. Acad. Sci. USA, 97: 3850 –3855, 2000.
262. Marshansky, V., Wang, X., Bertrand, R., Luo, H., Duguid, W.,
Chinnadurai, G., Kanaan, N., Vu, M. D., and Wu, J. Proteasomes
modulate balance among proapoptotic and antiapoptotic Bcl-2 family
members and compromise functioning of the electron transport chain in
leukemic cells. J. Immunol., 166: 3130 –3142, 2001.
263. Gardner, R. C., Assinder, S. J., Christie, G., Mason, G. G., Markwell,
R., Wadsworth, H., McLaughlin, M., King, R., Chabot-Fletcher, M. C.,
Breton, J. J., Allsop, D., and Rivett, A. J. Characterization of peptidyl
boronic acid inhibitors of mammalian 20 S and 26 S proteasomes and their
inhibition of proteasomes in cultured cells. Biochem. J. 346 Pt 2: 447– 454,
2000.
264. Almond, J. B., Snowden, R. T., Hunter, A., Dinsdale, D., Cain, K.,
and Cohen, G. M. Proteasome inhibitor-induced apoptosis of B-chronic
lymphocytic leukaemia cells involves cytochrome c release and caspase
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
550 Cellular Signaling Pathways as Therapeutic Targets
activation, accompanied by formation of an approximately 700 kDa
Apaf-1 containing apoptosome complex. Leukemia (Baltimore), 15:
1388 –1397, 2001.
265. Masdehors, P., Omura, S., Merle-Beral, H., Mentz, F., Cosset,
J. M., Dumont, J., Magdelenat, H., and Delic, J. Increased sensitivity of
CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br. J. Haematol., 105: 752–757,
1999.
266. Masdehors, P., Merle-Beral, H., Maloum, K., Omura, S., Magdelenat, H., and Delic, J. Deregulation of the ubiquitin system and p53
proteolysis modify the apoptotic response in B-CLL lymphocytes.
Blood, 96: 269 –274, 2000.
267. Chandra, J., Niemer, I., Gilbreath, J., Kliche, K. O., Andreeff, M.,
Freireich, E. J., Keating, M., and McConkey, D. J. Proteasome inhibitors
induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood, 92: 4220 – 4229, 1998.
268. Adams, J., Palombella, V. J., Sausville, E. A., Johnson, J., Destree,
A., Lazarus, D. D., Maas, J., Pien, C. S., Prakash, S., and Elliott, P. J.
Proteasome inhibitors: a novel class of potent and effective antitumor
agents. Cancer Res., 59: 2615–2622, 1999.
269. Hideshima, T., Richardson, P., Chauhan, D., Palombella, V. J.,
Elliott, P. J., Adams, J., and Anderson, K. C. The proteasome inhibitor
PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res., 61: 3071–3076,
2001.
270. Hideshima, T., Chauhan, D., Richardson, P., Mitsiades, C., Mitsiades,
N., Hayashi, T., Munshi, N., Dang, L., Castro, A., Palombella, V., Adams,
J., and Anderson, K. C. NF-␬ B as a therapeutic target in multiple myeloma.
J. Biol. Chem., 277: 16639 –16647, 2002.
271. Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Richardson,
P. G., Hideshima, T., Munshi, N., Treon, S. P., and Anderson, K. C.
Biologic sequelae of nuclear factor-␬B blockade in multiple myeloma:
therapeutic applications. Blood, 99: 4079 – 4086, 2002.
272. Sherr, C. J. The Pezcoller lecture: cancer cell cycles revisited.
Cancer Res., 60: 3689 –3695, 2000.
273. Sellers, W. R., Rodgers, J. W., and Kaelin, W. G., Jr. A potent
transrepression domain in the retinoblastoma protein induces a cell cycle
arrest when bound to E2F sites, Proc. Natl. Acad. Sci. USA, 92:
11544 –11548, 1995.
274. Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P.,
Lorain, S., Le Villain, J. P., Troalen, F., Trouche, D., and Harel-Bellan,
A. Retinoblastoma protein represses transcription by recruiting a histone
deacetylase. Nature (Lond.), 391: 601– 605, 1998.
275. Krug, U., Ganser, A., and Koeffler, H. P. Tumor suppressor genes
in normal and malignant hematopoiesis. Oncogene, 21: 3475–3495,
2002.
276. Sauerbrey, A., Stammler, G., Zintl, F., and Volm, M. Expression
of the retinoblastoma tumor suppressor gene (RB-1) in acute leukemia.
Leuk. Lymphoma, 28: 275–283, 1998.
277. Drexler, H. G. Review of alterations of the cyclin-dependent
kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human
leukemia-lymphoma cells. Leukemia (Baltimore), 12: 845– 859, 1998.
278. Chim, C. S., Liang, R., Tam, C. Y., and Kwong, Y. L. Methylation
of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J. Clin. Oncol., 19: 2033–2040,
2001.
279. Senderowicz, A. M. Development of cyclin-dependent kinase
modulators as novel therapeutic approaches for hematological malignancies. Leukemia (Baltimore), 15: 1–9, 2001.
280. Shapiro, G. I., and Harper, J. W. Anticancer drug targets: cell cycle
and checkpoint control. J. Clin. Investig., 104: 1645–1653, 1999.
281. Sausville, E. A., Arbuck, S. G., Messmann, R., Headlee, D., Bauer,
K. S., Lush, R. M., Murgo, A., Figg, W. D., Lahusen, T., Jaken, S., Jing,
X., Roberge, M., Fuse, E., Kuwabara, T., and Senderowicz, A. M. Phase
I trial of 72-hour continuous infusion UCN-01 in patients with refractory
neoplasms. J. Clin. Oncol., 19: 2319 –2333, 2001.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.
Modulation of Cellular Signaling Pathways: Prospects for
Targeted Therapy in Hematological Malignancies
Farhad Ravandi, Moshe Talpaz and Zeev Estrov
Clin Cancer Res 2003;9:535-550.
Updated version
Cited articles
Citing articles
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://clincancerres.aacrjournals.org/content/9/2/535
This article cites 276 articles, 158 of which you can access for free at:
http://clincancerres.aacrjournals.org/content/9/2/535.full.html#ref-list-1
This article has been cited by 3 HighWire-hosted articles. Access the articles at:
/content/9/2/535.full.html#related-urls
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer
Research.