Hindawi Publishing Corporation
Journal of Signal Transduction
Volume 2012, Article ID 123253, 14 pages
NPM-ALK: ThePrototypic Memberof a Family of Oncogenic
1Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada T6G 2E1
2Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada T6G 2B7
Correspondence should be addressed to Robert J. Ingham, email@example.com
Received 21 March 2012; Accepted 28 April 2012
Academic Editor: Rudi Beyaert
Copyright © 2012 Joel D. Pearson et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was
involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The
NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused
on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the
existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a
critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas,
and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy
in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and
discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine
three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL.
1.The ALK Receptor TyrosineKinase
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine
kinase of the insulin receptor superfamily, and in mice and
humans, the normal expression of ALK is largely restricted
appear to have no overt developmental abnormalities [5–8];
however, behavioural abnormalities have been noted in these
alcohol consumption and altered sensitivity to alcohol in
ALK-deficient mice compared to wild-type littermates .
Intriguingly, single-nucleotide polymorphisms (SNPs) in
ALK have been identified in humans that correlate with
decreased response to alcohol . A correlation between
ALK SNPs and schizophrenia has also been noted in a
Japanese study .
In Drosophila melanogaster, the jelly belly protein (Jeb)
has been characterized as an ALK ligand [10–12]. In mam-
mals, there does not appear to be a Jeb homologue but
two ligands for ALK have been described, pleiotrophin 
and midkine . However, there is not complete agree-
ment regarding whether these are indeed ALK stimulating
ligands [15, 16]. More recently, Perez-Pinera and colleagues
proposed an alternative mechanism by which pleiotrophin
could be stimulating ALK signalling. In their model, the
binding of pleiotrophin to its known receptor, receptor
tyrosine phosphatase β/ζ (RPTP β/ζ), relieves the inhibitory
dephosphorylation of ALK by RPTP β/ζ, thereby turning
on ALK signalling . ALK has also been suggested to be
a dependence receptor . Dependence receptors induce
apoptosis in their nonliganded state, but suppress apoptotic
signalling in response to ligand binding .
2.The Identification of NPM-ALK and Other
ALK-positive anaplastic large cell lymphomas (ALK+ ALCL)
are a distinct subset of non-Hodgkin lymphomas with a
T or null cell immunophenotype recognized by the World
2Journal of Signal Transduction
Health Organization Classification Scheme for hematologi-
cal neoplasms [58, 59]. These lymphomas express the CD30
(Ki-1) surface antigen, but the morphologic identification
of ALK+ ALCL can be challenging, as the cytologic features
of the tumor cells can be highly variable from case to case.
Nevertheless, the identification of the so-called “hallmark
cells,” which are characterized by a horseshoe- or kidney-
shaped nucleus and a prominent perinuclear Golgi body, can
facilitate the diagnosis [58, 59]. Regarding the pathobiology
of ALK+ ALCL, several groups in the late eighties and
early nineties noted that these lymphomas possessed a
recurrent chromosomal translocation, the t(2;5)(p23;q35)
translocation [60–64]. In 1994, it was demonstrated that this
translocation generates a fusion gene between a previously
uncharacterized tyrosine kinase on chromosome 2, and the
nucleophosmin (NPM) gene on chromosome 5 [20, 21]. This
kinase was termed ALK owing to its association with ALCL
and the expression of this kinase led to the identification of
ALCL. In addition to NPM, several other ALK translocation
partners have since been identified in ALK+ ALCL [23, 24,
27, 29–31, 33, 39, 42, 43, 45]. ALK fusion proteins have
also been reported in other cancers (Table 1). These cancers
include a portion of inflammatory myofibroblastic tumours
(IMT) [25, 32, 34, 43, 44, 46, 55, 65], nonsmall cell lung
carcinomas (NSCLC) [28, 49, 54, 57], diffuse large B-cell
lymphomas (DLBCL) [22, 35–37, 47, 48, 51], colon cancers
[50, 56], breast cancers , renal cell carcinomas [26, 52,
53], and extramedullary plasmacytomas . Two papers
also reported detecting tropomyosin 4- (TPM4-)ALK fusion
protein expression in some cases of esophageal squamous
cell carcinoma [40, 41]. Moreover, it has very recently been
established that inhibitors of ALK are effective at treating
patients with ALK+ ALCL  and other malignancies
expressing ALK fusion proteins [67, 68]. Although not a
focus of this paper, ALK has been reported to be highly
expressed in breast cancer , and ALK gene amplifications
and activating mutations have been identified in familial
and sporadic neuroblastoma [70–75] and thyroid cancer
termed NPM-ALK whose transcription is under the control
of NPM regulatory sites. NPM is a ubiquitously expressed
protein that is predominately found in the nucleolus ,
but can shuttle between the cytoplasm and nucleus .
NPM is multifunctional and regulates several cellular activ-
ities including transcription, ribosome biogenesis, and the
shuttling of proteins between the nucleus and cytoplasm
. The NPM-ALK fusion gene consists of the first four
exons of NPM which encodes for the first 117 amino acids
of the NPM protein, and the ALK portion of the fusion
includes the exons encoding for the intracellular tail and
kinase domain of ALK . Importantly, the NPM part of
the fusion includes the NPM dimerization/oligomerization
domain [80, 81]. As we will discuss in the next section, this
domain is critically important for NPM-ALK activity, and
the presence of a dimerization/oligomerization domain is a
common feature of other ALK fusion partners.
Table 1: Identified ALK fusion proteins and their associated malig-
identified in are indicated. ALCL: anaplastic large cell lymphoma;
DLBCL: diffuse large B-cell lymphoma; IMT: inflammatory myofi-
broblastic tumour; NSCLC: nonsmall cell lung carcinoma; RCC:
renal cell carcinoma; SCC: squamous cell carcinoma.
ALCL, IMT, RCC
ALCL, DLBCL, IMT,
IMT, ALCL, SCC
[26, 28, 49, 50]
3.The Importance of
An essential role for the NPM portion of NPM-ALK was
first demonstrated by experiments showing that deletion of
the entire NPM region of NPM-ALK generated a protein
incapable of transforming NIH 3T3 cells . Similarly,
Bischof et al. demonstrated that NPM truncation or deletion
mutants were not tyrosine phosphorylated and were unable
to transform Fischer Rat 3T3 cells . Since NPM has been
reported to form hexamers and other oligomers [82, 83],
researchers examined whether NPM could be providing an
oligomerization domain in NPM-ALK. Indeed, gel filtration
 and sucrose gradient  experiments demonstrated
that NPM-ALK forms oligomeric complexes in an NPM-
dependent manner. Moreover, NPM-ALK can dimerize with
endogenous NPM, and it is believed that this accounts for
why some NPM-ALK is observed in the nucleus .
The basic domain of Echinoderm microtubule-associat-
ed protein-like 4 (EML4) also functions as a dimerization
domain in EML4-ALK , and this is likely mediated by
Journal of Signal Transduction3
Table 2: Known or suspected dimerization/oligomerization do-
mains in ALK fusion partners. Dimerization/oligomerization do-
mains present ALK fusion partners that are postulated to mediate
dimerization/oligomerization are indicated. With the exception of
the basic domain of EML4-ALK, these domains have not been
experimentally proven to mediate dimerization/oligomerization of
the respective fusion proteins. The basic domain of EML4 also
possesses a coiled-coil motif which is postulated to mediate dimer-
Triskelion assembly motifs
∗The MYH9 coiled-coil domain is truncated in the fusion protein and may
not be functional.
a coiled-coil motif within the basic domain . Most other
ALK fusion partners possess known dimerization/oligom-
erization domains that are postulated to mediate dimeriza-
tion/oligomerization of the fusion proteins (Table 2). MSN-
ALK (a fusion between moesin and ALK) appears not to
have an oligomerization domain and is postulated to be
activated through the colocalization of MSN-ALK fusion
proteins to cellular membranes . Thus, dimerization,
oligomerization, or colocalization of ALK fusion proteins
oncoproteins to signal.
NPM-ALK activates downstream signalling events that pro-
mote proliferation, prevent apoptosis, and enhance migra-
tion in ALK+ ALCL (reviewed in [5, 85, 86]). We will
focus on the STAT3, MEK/ERK, and PI3K/Akt pathways, as
much is known about the role these pathways play in ALK+
ALCL pathogenesis. In particular, we will discuss the cellular
they are regulated by NPM-ALK signalling.
5.The STAT3 Pathway
Members of the signal transducer and activator of transcrip-
tion (STAT) family of transcription factors are activated by
interferon, cytokine, and growth factor receptor signalling
. The tyrosine phosphorylation of STATs by tyrosine
kinases, particularly the Janus kinases (JAKs), facilitates the
dimerization of STATs. This allows the STATs to translocate
to the nucleus and promote the transcription of genes
involved in proliferation, cell survival, and the immune
response [87, 88]. In ALK+ ALCL, the activation of STAT3
has been strongly implicated in the pathogenesis of this lym-
phoma (Figure 1).
STAT3 is activated in ALK+ ALCL cell lines and patient
samples [89–91], as well as cells isolated from NPM-ALK
transgenic mice [92, 93], as measured by its phosphorylation
on tyrosine 705. The inhibition of STAT3 in ALK+ ALCL
cell lines, either through the overexpression of a dominant-
negative STAT3 construct  or decreasing STAT3 expres-
sion using antisense oligonucleotides , resulted in
decreased proliferation and the induction of apoptosis.
STAT3 was also required for NPM-ALK to transform mouse
embryo fibroblasts, and for the continued survival of T-cell
lymphomas induced in mice by the expression of an NPM-
ALK transgene .
regulating the expression of multiple genes. Microarray
studies performed by Piva and colleagues demonstrated
that knockdown of STAT3 altered the expression of ∼1500
genes in a variant of the SUP-M2 ALK+ ALCL cell line
. Importantly, STAT3 functions both as an activator
and repressor of transcription, and approximately 60% of
the STAT3-regulated genes identified by Piva et al. were
repressed by STAT3 . Several additional studies have
identified STAT3 regulated genes in ALK+ ALCL. Those
genes found to be upregulated by STAT3 include: genes
that promote proliferation such as Cyclin D1, Cyclin D3, c-
Myc, ICOS, C/EBPβ [93–97]; those that promote survival
such as Bcl-xL, Survivin, Bcl-2, Mcl-1, Bcl2A1, C/EBPβ [90,
93, 97, 98]; others including CD30, PD-L1, TIMP-1, Socs3,
is also responsible for repressing the expression of T-cell
genes that are commonly not expressed in ALK+ ALCL
including CD3ε, ZAP-70, LAT, and SLP-76, and it appears
to do so in part through the upregulation of DNA methyl-
transferases (DNMTs) . DNMTs methylate CpG motifs
in promoter regions of genes, and this blocks the binding
of some transcription factors and facilitates the recruitment
of Methyl-C binding proteins to these promoters. methyl-
C binding proteins can then recruit histone deacetylases
and methyltransferases that convert promoter regions into
transcriptionally inactive heterochromatin . Zhang and
colleagues demonstrated that STAT3 also promotes the
binding of DNMTs 1–3 to the IL2Rγ promoter in order
to repress IL2Rγ gene expression . Silencing IL2Rγ
chain expression appears to be critical in ALK+ ALCL as re-
in decreased NPM-ALK expression and reduced viability
. This study also demonstrated that STAT3 enhances
targeting microRNA, miR-21. STAT3 is also responsible for
the epigenetic silencing of STAT5A in ALK+ ALCL, which
prevents STAT5A from repressing NPM-ALK expression and
thereby interfering with NPM-ALK signalling . Given
the importance of STAT3 transcriptional activity in ALK+
4Journal of Signal Transduction
Figure 1: The STAT3 signalling pathway in ALK+ ALCL. STAT3 is activated by NPM-ALK signalling, but reports differ as to whether this is
JAK3-dependent or independent. The phosphatase, PP2A, and signalling through the IL-9, IL-21, and IL-22 receptors also promote STAT3
activation in ALK+ ALCL. STAT3 promotes the expression of genes that suppress apoptosis and enhance proliferation in ALK+ ALCL.
STAT3 can also repress a variety of genes in this malignancy through DNA methylation. Suppression of the SHP1 phosphatase by STAT3 is
particularly important in ALK+ ALCL, as SHP1 inhibits NPM-ALK and STAT3 activity.
ALCL, it is not surprising that many mechanisms contribute
to the activation of STAT3 in this lymphoma.
STAT3 [89, 109] and JAK3  have both been shown
to coimmunoprecipitate with NPM-ALK, and several studies
have shown that NPM-ALK promotes the tyrosine phos-
phorylation of STAT3 [89, 90, 92, 93]. However, there is
not complete agreement regarding whether STAT3 tyrosine
phosphorylation is JAK3 dependent [94, 110], or whether
STAT3 is tyrosine phosphorylated in a JAK3-independent
NPM-ALK . The serine/threonine phosphatase PP2A
has also been implicated in positively regulating STAT3
activity in ALK+ ALCL, as inhibition of PP2A activity
with Calyculin A was demonstrated to reduce STAT3 tyro-
sine phosphorylation . STAT3 signalling is also likely
enhanced in this lymphoma due to the fact that ALK+
ALCL cell lines do not express the STAT3 inhibitor, PIAS3
. Moreover, the SHP-1 tyrosine phosphatase is often
silenced by DNA methylation in ALK+ ALCL [112, 113],
and this is likely due in part to the recruitment of DNMTs
Journal of Signal Transduction5
and histone deacetylases to the SHP-1 promoter by STAT3
. Silencing SHP-1 in ALK+ ALCL is important as SHP-
1 negative regulates NPM-ALK signalling through either the
direct or indirect dephosphorylation of NPM-ALK, JAK2,
and STAT3 [114–116], and the targeting of NPM-ALK for
proteasomal degradation [115, 116].
Cytokine signalling also plays a role in regulating STAT3
activity in ALK+ ALCL. Signalling through the IL9 ,
IL21 , and IL22  receptors has been shown to
promote STAT3 activation in this lymphoma, and much
of this may be due to autocrine signalling. Furthermore,
the expression of the IL22R1 subunit of the IL22 receptor
is promoted by NPM-ALK, demonstrating a link between
NPM-ALK and cytokine signalling in this lymphoma .
Since the IL9 and 21 receptors utilize the IL2R common
γ chain, these findings still need to be reconciled with the
results of Zhang and colleagues which found that the IL2Rγ
chain is silenced in ALK+ ALCL .
Signalling mediated by the extracellular signal-regulated
kinases 1 and 2 (ERK1 and 2) promotes proliferation, sur-
vival, differentiation, and migration . These serine/
threonine kinases are activated by many growth factor recep-
tors through a well-defined kinase cascade. This kinase cas-
cade is initiated by the activation of the Ras GTPase, which
activates the Raf-1 serine/threonine kinase. Raf-1 then acti-
vates the dual specificity kinases, MAPK/Erk kinases 1 and 2
(MEK1 and 2), which phosphorylate and activate the ERKs
The ERK pathway is activated in ALK+ ALCL cell lines
and patient samples [122, 123] and plays a central role in
promoting cell proliferation and suppressing apoptosis in
this cancer (Figure 2). Treatment with the MEK1/2 inhibitor,
U0126, was found to reduce proliferation [123–125] and
enhance apoptosis [124, 125] in ALK+ ALCL cell lines.
Reduced proliferation was also evident when the Karpas
299 ALK+ ALCL cell line was treated with ERK1 and/or 2
siRNA . However, only the silencing of ERK1 in these
cells was found to increase apoptosis . Two important
downstream mediators of MEK/ERK signalling in ALK+
ALCL are the serine/threonine kinase, mammalian target of
rapamycin (mTOR), and the JunB transcription factor.
The mTOR pathway has been demonstrated to be acti-
vated in ALK+ ALCL patient samples, as measured by phos-
phorylation of mTOR [125, 126] and downstream targets
of mTOR signalling [123, 125–127]. Marzec and colleagues
found that treatment of the SU-DHL-1 ALK+ ALCL cell line
with MEK inhibitors or ERK1/2 siRNA resulted in reduced
phosphorylation of the ribosomal S6 protein (RPS6) .
RPS6 is a downstream target of mTOR signalling, and phos-
phorylation of RPS6 promotes cell growth . The p70
S6 kinase (p70S6K), which is activated by mTOR and phos-
phorylates RPS6, is also inhibited in SU-DHL-1 cells treated
with U0126 , but surprisingly not in the SR-786 ALK+
ALCL cell line . MEK/ERK signalling was postulated to
activate mTOR through inhibition of the tuberous sclerosis
complex (TSC) . TSC is a GTPase-activating protein
that inhibits mTOR through inactivating the Rheb GTPase
. The notion that MEK/ERK signalling inhibits TSC in
ALK+ ALCL is supported by the finding that treatment of
SU-DHL-1 cells with MEK inhibitors resulted in decreased
phosphorylation of TSC2 on inhibitory serine 1798 .
The activation of mTOR and the phosphorylation of mTOR
substrates, eukaryotic initiation factor 4E-binding protein-
1 (4E-BP1) and p70S6K, has also been demonstrated to
be dependent on PI3K and Akt activity in ALK+ ALCL
. Phosphorylation of 4E-BP1 by mTOR results in the
dissociation of 4E-BP1 from eukaryotic initiation factor 4E
(EIF4E), which allows EIF4E to initiate translation .
However, the importance of the PI3K/Akt pathway in the
activation of mTOR in ALK+ ALCL has been questioned
Treatment of ALK+ ALCL cell lines with the mTOR in-
hibitor, rapamycin, resulted in reduced proliferation [123,
125–127, 129] and the induction of apoptosis [126, 127].
siRNA-mediated knockdown of mTOR was similarly found
to reduce proliferation and enhance apoptosis in ALK+
ALCL cell lines . Decreased proliferation as a result of
mTOR inhibition is at least in part due to the dephosphory-
kinase inhibitors, p27kip1and p21waf 1. Increased
apoptosis in response to rapamycin treatment is likely due to
xL, Mcl-1, and c-FLIP . Inhibition of mTOR was also
demonstrated to reduce the size of NPM-ALK-expressing
murine tumours in immunocompromised mice .
The transcription of JunB is also promoted by MEK sig-
1 transcription factor . Interestingly, mTOR signalling
cell lines through the targeting of JunB mRNA to ribosome-
rich polysomes . JunB is an AP-1 family transcription
factor that is highly expressed in ALK+ ALCL cell lines and
patient samples [134–136] and has been shown to promote
the proliferation of the Karpas 299 ALK+ ALCL cell line
. JunB also influences phenotypic characteristics of this
lymphoma through promoting the transcription of CD30
[122, 137] and the Granzyme B serine protease . CD30
signalling also activates MEK/ERK/JunB signalling in this
lymphoma to further promote CD30 expression .
The activation of Raf-1, MEK, and ERK in ALK+ ALCL
cell lines is dependent on NPM-ALK activity [124, 139],
and the ectopic expression of NPM-ALK has also been
demonstrated to induce the activation of these proteins
[123, 124, 140, 141]. NPM-ALK can activate Ras when
ectopically expressed in the Jurkat T leukemia cell line, and
the expression of a dominant negative N17 Ras decreased
NPM-ALK-dependent NF-AT/AP-1 luciferase activity in
Jurkat cells. Furthermore, treatment of the SU-DHL-1 ALK+
ALCL cell line with the Ras inhibitor, FTI-277, resulted
in increased apoptosis and decreased proliferation .
Several mechanisms for how NPM-ALK activates Ras have
been postulated. The Ras activator, Son of Sevenless (SOS),
has been argued to be recruited to NPM-ALK via the adapter
6Journal of Signal Transduction
to activate MEK/ERK appears not to be dependent on Raf-1. Rather, another MAP3K, Cot, may be important for activation of MEK/ERK
in ALK+ ALCL, but it is not known whether Cot is activated by NPM-ALK signalling. The activation of ERK1/2 promotes ALK+ ALCL
proliferation and survival, largely through the JunB transcription factor and serine/threonine kinase, mTOR. ERK1/2 activates the ETS-1
transcription factor which promotes the transcription of JunB. JunB promotes the transcription of CD30 and Granzyme B in this lymphoma,
but likely has other important targets that have not yet been identified. ERK1/2 are thought to activate mTOR signalling in ALK+ ALCL by
phosphorylating and inhibiting TSC1/2. mTOR phosphorylates and inhibits the cell cycle inhibitor, Rb. It also phosphorylates and activates
p70S6K which phosphorylates RPS6 to promote cell growth. mTOR also influences the expression of genes that contribute to the survival
and proliferation of ALK+ ALCL cells. MEK/ERK are also activated by signalling through CD30 in ALK+ ALCL, and this leads to enhanced
Journal of Signal Transduction7
protein Grb2 by molecules such as Shc, SHP2, and insulin
receptor substrate-1 (IRS-1) [80, 141–143]. Ras activation
has also been proposed to occur through a PLCγ-dependent
activation of Ras guanyl nucleotide-releasing protein (Ras-
GRP) . While Raf-1 is activated by NPM-ALK, it does
not appear to be required for ERK activation in ALK+ ALCL
cell lines . Another MAP3K, Cot/MAP3K8, may be the
primary activator of MEK in this lymphoma. Treatment of
the SU-DHL-1 cell line with Cot siRNA or a Cot inhibitor
decreased ERK and mTOR activation and reduced cellular
proliferation . Whether Cot is regulated by NPM-ALK
was not investigated in this study.
7.The PI3K/Akt Pathway
The phosphatidylinositol 3?-kinase (PI3K)/Akt pathway reg-
ulates cell growth, differentiation, apoptosis, metabolism,
a regulatory p85 subunit and a catalytic p110 subunit, and
this enzyme phosphorylates inositol phospholipids on the 3?
position of the inositol ring [144, 145]. These lipids, in turn,
activate a number of Pleckstrin Homology (PH) domain-
containing proteins; most notably the serine/threonine
kinase Akt [144, 145].
Signalling through the PI3K pathway promotes cell sur-
vival and proliferation in ALK+ ALCL (Figure 3). Treatment
of ALK+ ALCL cell lines or Ba/F3 cells ectopically expressing
NPM-ALK with PI3K inhibitors induces apoptosis and
reduces proliferation [146, 147]. PI3K inhibitors also inhibit
the transformation of Rat-1 fibroblasts by NPM-ALK ,
and a dominant negative p85 subunit unable to associate
with the p110 subunit was demonstrated to inhibit the
ability of NPM-ALK-expressing Ba/F3 cells to form colonies
in methylcellulose . Several downstream targets are
regulated by PI3K in ALK+ ALCL.
The Akt substrate, glycogen synthase kinase-3β (GSK-
3β), is an important target of NPM-ALK signalling in
ALK+ ALCL. Phosphorylation of GSK-3β on serine 9 by
Akt inhibits GSK-3β activity , and in ALK+ ALCL
this has been argued to be important for preventing GSK-
3β from phosphorylating, and targeting for degradation,
the antiapoptotic protein Mcl-1 and the positive cell cycle-
regulator, phosphatase CDC25A . Furthermore, this
study showed that phosphorylation of GSK-3β on ser-
ine 9 correlated with elevated CDC25A levels in ALK+
ALCL patient tumour biopsies. A separate study also
through PI3K, through either transcriptional upregulation
of CDC25A or enhanced CDC25A mRNA stability .
Further supporting the notion that inhibition of GSK-3β is
an important target of NPM-ALK signalling, treatment of
ALK+ ALCL cell lines with either GSK-3β shRNA or a GSK-
3β inhibitor could partially rescue the decreased viability
associated with ALK inhibitor treatment .
NPM-ALK/PI3K/Akt signalling also activates the sonic
hedgehog (SHH) pathway in ALK+ ALCL . SHH
is a secreted molecule that, when bound to its receptor
Patched, relieves inhibition of the Smoothened co-receptor
by Patched. This allows Smoothened to activate glioma-
associated homologue (GLI) transcription factors .
SHH and GLI1 were found to be highly expressed in
primary ALK+ ALCL patient samples, and their expression
in cell lines was dependent on NPM-ALK and PI3K activity
. It was argued in this study that PI3K-mediated
activation of Akt is important for inhibiting GSK-3β in
order to prevent GSK-3β from phosphorylating GLI1 and
targeting the protein for proteasomal degradation. NPM-
ALKwasalsofoundto enhanceGLI1 transcriptional activity,
and expression of the GLI1 target gene, cyclin D2 .
Moreover, the inhibition of GLI1 in ALK+ ALCL cell lines,
either through siRNA-mediated knockdown or treatment
of cells with a Smoothened inhibitor, reduced viability and
arrested cells in the G1 stage of the cell cycle .
Another target of Akt signalling in ALK+ ALCL is the
FOXO3a transcription factor . The phosphorylation of
FOXO3a by Akt results in its binding to 14-3-3 proteins,
to promote transcription . FOXO3a is phosphorylated
in ALK+ ALCL cell lines and in cells ectopically express-
ing NPM-ALK . Accordingly NPM-ALK signalling
results in the down-regulation of the pro-apoptotic protein,
Bim-1 and the cell cycle-inhibitor, p27kip1, which
are transcriptional targets of FOXO3a [155, 156]. NPM-
ALK/PI3K/Akt signalling also maintains low levels of p27kip1
by phosphorylating p27kip1, and thereby targeting p27kip1for
proteasomal degradation [157, 158].
The activation of the PI3K pathway in ALK+ ALCL
is largely dependent on the activity of NPM-ALK. PI3K
complexes with NPM-ALK in ALK+ ALCL cell lines [146,
147, 159] and cells isolated from NPM-ALK transgenic mice
. Akt is activated in ALK+ ALCL cell lines and patient
samples . The activation of Akt in this lymphoma is
dependent on NPM-ALK and PI3K activity [126, 127, 160],
and Akt activity is upregulated in a PI3K-dependent manner
by ectopically expressed NPM-ALK in Ba/F3 cells [127, 146,
153]. PTEN, a lipid phosphatase that dephosphorylates PI3K
lipid products [144, 145], is not expressed in some ALK+
ALCL patient samples, and this may be a contributing factor
to Akt activation in these patients .
It has been over 15 years since the discovery of the NPM-
ALK oncoprotein. In this time we have learned much about
the signalling pathways activated by NPM-ALK in ALK+
ALCL, and how these pathways contribute to proliferation
and survival of this lymphoma. This information has been
critical in directing research towards understanding how
ALK translocations signal and function in other malig-
nancies. For example, STAT3 activation has been observed
in clathrin heavy chain- (CTLC-)ALK-expressing DLBCL
patient samples , and STAT3, ERK, and AKT are
active in EML4-ALK-expressing NSCLC cell lines [163–165];
however, the importance of these pathways in NSCLC and
their regulation by EML4-ALK appears to vary amongst
NSCLC cell lines [163–165]. Yet, even if activation of
8Journal of Signal Transduction
Figure 3: The PI3K/Akt signalling pathway in ALK+ ALCL. NPM-ALK associates with and activates PI3K, which, in turn, activates the
serine/threonine kinase Akt. Expression of the PTEN lipid phosphatase, which inhibits PI3K signalling, is lost in some ALK+ ALCL tumour
samples and likely contributes to Akt activation in cancers where PTEN is not expressed. Akt inhibits GSK3β activity in ALK+ ALCL, which
protects GLI1, Mcl-1, and CDC25A from proteasomal degradation. Akt also phosphorylates the cell-cycle inhibitor, p27kip1, in ALK+ ALCL
and this results in the targeting of p27kip1for proteasomal degradation. Phosphorylation of the FOXO3a transcription factor by Akt results
in the binding of FOXO3a to 14-3-3 proteins. This sequesters FOXO3a in the cytoplasm, preventing it from translocating to the nucleus and
transcribing pro-apoptotic and cell cycle inhibitory genes. In addition to being an important downstream target of MEK/ERK signalling in
ALK+ ALCL, mTOR activity may also be promoted by PI3K/Akt signalling. NPM-ALK/Akt signalling also promotes the expression of SHH.
When SHH binds its receptor, Patched (PTCH), this relieves the inhibition of the Smoothened (SMO) coreceptor by Patched. This allows
Smoothened to activate the GLI1 transcription factor, which promotes the transcription of the proproliferation protein, Cyclin D2.
the STAT3, ERK, and PI3K/Akt pathways is common to
malignancies expressing ALK fusion proteins, differences
almost certainly exist in the genes regulated by these
pathways in the individual cancers. Some of these differences
may be important in the pathogenesis of their respective
malignancies. Thus, a more thorough characterization of
these signalling pathways in other ALK fusion protein-
expressing malignancies needs to be a priority of future
While the information gained from elucidating how
NPM-ALK signals in ALK+ ALCL has been, and will
continue to be, beneficial for understanding how other ALK
fusion proteins signal, it is clear that these fusion proteins
are not identical in their signalling capability. In a study
by Armstrong and colleagues, NIH 3T3 cells expressing
the NPM-, Trk-fused gene (TFG)-, 5-aminoimidazole-4-
drolase (ATIC)-, tropomyosin 3 (TPM3)-, or CTLC-ALK
Journal of Signal Transduction9
fusion proteins at roughly equal levels, differed in their
ability to activate STAT3 and Akt . The proliferation
rate, invasiveness, and ability to form tumours in nude
mice also differed amongst the cells expressing the differ-
ent ALK fusion proteins . Similarly, gene expression
profiling demonstrated that, while tumours from ALK+
ALCL patients expressing NPM-ALK or TPM3-ALK shared
many commonly regulated genes, distinctly regulated genes
were observed . Accordingly, a second focus of future
research needs to be a more detailed examination of whether
distinctions exist in the signalling pathways or cellular
processes regulated by different ALK fusion proteins within
the same malignancy.
The authors would like to apologize to any colleague whose
work they were unable to discuss. R. J. Ingham’s laboratory is
funded by an operating grant from the Alberta Cancer Foun-
dation/Alberta Innovates Health Solutions. J. D. Pearson is a
recipient of an Alberta Cancer Foundation Studentship. J. T.
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