Leukemia (2006) 20, 572–582. doi:10.1038/sj.leu.2404125; published online 16 February 2006

Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells

S D Turner1 and D R Alexander2

  1. 1Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Lab Block Level 3, Addenbrooke's Hospital, Cambridge, UK
  2. 2Laboratory of Lymphocyte Signalling and Development, Babraham Research Campus, The Babraham Institute, Babraham, Cambridge, UK

Correspondence: Dr SD Turner, Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Lab Block Level 3, Addenbrooke's Hospital, Box 231, Cambridge CB2 2QQ, UK. E-mail:

Received 13 October 2005; Revised 6 December 2005; Accepted 20 December 2005; Published online 16 February 2006.



The fusion tyrosine kinases (FTKs) are generated by chromosomal translocations creating bipartite proteins in which the kinase is hyperactivated by an adjoining oligomerization domain. Autophosphorylation of the FTK generates a 'signalosome', an ensemble of signalling proteins that transduce signals to downstream pathways. At the earliest stages of oncogenesis, FTKs can mimic mitogenic cytokine signalling pathways involving the GAB-2 adaptor protein and signal transducers and activators of transcription (STAT) factors, generating replicative stress and thereby promoting a mutator phenotype. In parallel, FTKs couple to survival pathways that upregulate prosurvival proteins such as Bcl-xL, so preventing DNA-damage-induced apoptosis. Following transformation, FTKs induce resistance to genotoxic attack by upregulating DNA repair mechanisms such as STAT5-dependent RAD51 transcription. The phenomenon of 'oncogene addiction' reflects the continued requirement of an active FTK 'signalosome' to mediate survival and mitogenic signals involving the PI 3-kinase and mitogen-activated protein stress-activated protein kinase pathways, and the nuclear factor-kappa B, activator protein 1 and STAT transcription factors. The available data so far suggest that FTKs, with some possible exceptions, induce and maintain the transformed state using similar panoplies of signals, a finding with important therapeutic implications. The FTK signalling field has matured to an exciting phase in which rapid advances are facilitating rational drug design.


oncogene, tyrosine kinase, NPM-ALK, Bcr-Abl, Tel-PDGFbetaR, Tel-Jak2



About 30 of the 90 protein tyrosine kinases in the human genome have been implicated in cancer.1 These oncogenic tyrosine kinases (OTKs) are thought to induce either directly or indirectly a critical repertoire of transforming events, namely, uncontrolled cell growth, genomic instability and protection of DNA-damaged cells from apoptosis.1, 2 It remains possible, although is not yet proven, that all OTKs induce this same ensemble of oncogenic cellular dysfunctions, albeit by somewhat different molecular routes. The lineage specificity of OTK expression, and their levels and timing of expression are, in addition, all likely to be critical in determining the heterogeneous clinical consequences that arise from the kinase-mediated transforming events.

The fusion tyrosine kinases (FTKs) are generated by chromosomal translocations and represent an important subclass of the kinases that transform haematopoietic lineages. In this review, we address the question as to whether different FTKs utilize essentially the same signalling pathways to transform haematopoietic cells and, in addition, to maintain tumour growth and survival following transformation. The answer to this latter question is critical in predicting the potential responsiveness of different tumour types to novel therapeutic interventions. We provide a brief overview of the major FTKs implicated in haematological malignancies, illustrated in Figure 1 and Table 1, before discussing the key oncogenic signals that they induce.

Figure 1.
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The structure of fusion tyrosine kinases (FTKs). The Bcr-Abl FTK has three splice variants creating proteins of 190, 210 and 230 kDa. All three variants share oligomerization domains (OD), serine/threonine kinase (S/T kinase), Src homology 3 (SH3), DNA binding (DNA), tyrosine kinase (TYR kinase) and acidic binding (AB) domains. In addition, the p210 and p230 isoforms have Pleckstrin homology (PH) and Dbl homology (Dbl) domains. The other FTKs have in common with Bcr-Abl the OD and TYR kinase domains and, in addition, nucelophosmin-anaplastic lymphoma kinase (NPM-ALK) has a metal binding (MB) domain; Tel-JAK2 a janus kinase homology 2 (JH2) domain; and Tel-PDGFR has a helix-loop-helix (HLH) motif and a transmembrane domain (TM). The OD domain in each case is responsible for the oliogomerization and hence hyperactivation of the TYR kinase.

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FTKS that transform haematopoietic lineages

Breakpoint cluster region-Abelson leukaemia (Bcr-Abl)

Bcr-Abl is the protein product of the Philadelphia chromosome (t(9;22)) and is present in alternatively spliced forms creating proteins of 230, 210 and 190 kDa, the two larger versions containing more of the Bcr gene product than the p190 form28 (Figure 1). Abl is a ubiquitously expressed non-receptor tyrosine kinase located in both the cytoplasm and the nucleus, although mainly in the cytoplasm. In the cytoplasm, Abl binds the actin cytoskeleton and is involved in cytoskeletal moulding, whereas the nuclear localization is associated with the regulation of the cell cycle.1 The N-terminal portion of Abl is lost in the t(9;22) translocation resulting in constitutive activation of the kinase.1 The Bcr gene encodes a protein with a ser/thr kinase domain, a Guanine nucleotide exchange factor (GEF) domain and also a Guanine nucleotide activating protein domain. The first exon containing the serine/threonine kinase is retained in all forms of Bcr-Abl and, in addition, the GEF domain is retained in the two larger forms (Figure 1).

The p190 and p210 Bcr-Abl isoforms are best characterized for their association with leukaemias, including chronic myelogenous leukaemia (CML) and acute leukaemias which express Bcr-Abl in one form or another.29 Bcr-Abl+ CML has a varied prognosis with survival after diagnosis ranging from one to more than 10 years.29 The p230 form of Bcr-Abl is associated with a neutropenic leukaemia.30 Different Abl fusion partners have been detected in human leukaemias (cf. Table 1), including Tel, also known as ETV6, described further below.29

Nucelophosmin-anaplastic lymphoma kinase

NPM-ALK is an 80 kDa protein generated by a t(2;5) chromosomal translocation which results in the N-terminus of nucleophosmin (NPM) fusing with the cytoplasmic tail of the transmembrane receptor anaplastic lymphoma kinase (ALK)4 (Figure 1). NPM-ALK locates to both cytoplasmic and nuclear compartments, although its cytoplasmic localization alone is sufficient for transformation.31 NPM is a ubiquitously expressed ribonuclear shuttle protein involved in the regulation of centrosome duplication and p53 activity,32, 33 whereas ALK is a receptor of unknown function, restricted in expression to developing neuronal tissue,34 with ligands recently identified as pleiotrophin and midkine.35 The highly conserved ALK protein has a Drosophila homologue, alk, which is involved in visceral muscle formation.36, 37 The NPM-ALK fusion protein retains the oligomerization domain of NPM and the kinase domain of ALK, resulting in hyperactivation of the ALK kinase in lymphoid tissues. Other fusion partners besides NPM have been described but are relatively rare compared to NPM-ALK.38

NPM-ALK expression characterizes a rare form of non-Hodgkin's lymphoma, anaplastic large-cell lymphoma (ALCL), typically of a T or null cell origin, presenting mainly in children and young adults and with a relatively good prognosis.39 More recently ALK expression has been noted in plasmablastic lymphomas either in the form of NPM-ALK or fused to other activating partners.40 ALK has also been detected in neuroblastomas and immunomyofibroblastic tumours, although the functional significance of this is not yet known.20, 41

Ets variant gene 6-janus kinase 2 (Tel(ETV6)-Jak2)

Chromosomal translocations between chromosomes 9 and 12 have been detected in extremely rare cases of both acute lymphoblastic leukaemia (t(9;12)) and CML-like disease (t(9;15;12)) resulting in the fusion of the Tel protein to the JH1 domain of Janus kinase 2 (Jak 2).5, 6 Tel is a member of the Ets family of transcription factors and consists of an amino-terminal pointed domain (PNT) which is retained in the fusion protein. The PNT domain mediates homotypic oligomerization of the fusion protein, resulting in its activation.

Ets variant gene 6-platelet-derived growth factor beta receptor (Tel(ETV6)-PDGFbetaR)

Tel-PDGFbetaR expression is associated with chronic myelomonocytic leukaemia (CMML).7 The Tel-PDGFbetaR protein results from a t(5;12) chromosomal translocation and consists of the Tel N-terminus fused to the transmembrane and intracellular kinase domains of the PDGFbeta receptor7 (Figure 1). The physiological ligand for the PDGFbetaR in normal cells is PDGF-BB, which induces dimerization and hence activation of the kinase with subsequent autophosphorylation, thereby creating docking sites for SH2 domain-containing proteins.42 In contrast, the fusion protein is activated independently of ligand by the PNT domain of Tel, is detected in the cytosol and does not appear in the nucleus as does full-length Tel, nor in the membrane as does full-length PDGFbetaR.43

Ets variant 6-neurotrophic growth factor receptor 3 (Tel-TRKC or Tel-NTRK3)

Tel, as outlined above is also found juxtaposed to TRKC, a member of the neurotrophic growth factor receptor family, which acts as a receptor for neurotrophin 3 and is essential for normal neural development.44, 45 This fusion protein, like NPM-ALK, is detected not only in solid tumours (infantile fibrosarcoma) but also in acute myeloid leukaemia (AML), the former excluding exons 1–5 of Tel and incorporating a 42 bp exon of TRKC not included in the AML form.9, 46

Other FTKs

The advent of better techniques to detect chromosomal translocations has resulted in the discovery of a number of additional FTKs implicated in the development of myelodysplasias, leukaemias and lymphomas, some of which are listed in Table 1. These include Tel-FGFR3, Tel-ARG, Tel-Syk, PCM1-Jak2 and TIF1-FGFR1. At present, there is very little information available regarding the transforming signals mediated by these fusion proteins.


FTK-induced signalling pathways in transformation

The universal retainment of an oligomerization domain in each of the FTKs provides a common mechanism for activation. Homotypic oligomerization induces fusion protein autophosphorylation, generating docking sites for SH2 domain-containing proteins, hence activating a plethora of downstream signalling pathways that lead to the transforming events illustrated in Figure 2. Investigation of FTK-induced oncogenic signals in primary non-transformed cells has been restricted largely to transgenic mouse models, adoptive transfer systems and transduction of genes of interest directly into primary cells. The rapidly growing literature using these approaches is helping to elucidate the very earliest events in the transforming process. The signalosomes generated by the FTKs (illustrated in Figure 3) suggest that mitogenic pathways are central to the transforming process.

Figure 2.
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Mechanisms of transformation induced by fusion tyrosine kinases (FTKs) in haemopoietic cells. The majority of data so far pertains to the breakpoint cluster region-Abelson leukaemia (Bcr-Abl) FTK and demonstrates that the induction of mitogenic signals are central to the transforming process. The hypothesized replicative stress induced leads to the induction of a status of genomic instability and the acquisition of additional mutations and chromosomal aberrations, which may result in the production/expression of other oncogenes and/or the inactivation of tumour suppressor genes.

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Figure 3.
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Survival and mitogenic pathways induced in fusion tyrosine kinase (FTK)-transformed cells. FTK-transformed cells survive despite high levels of DNA damage as a result of the upregulation of survival pathways as described in the text. In addition, FTK-transformed cells proliferate and overcome cell cycle blocks as a result of the mitogenic signals induced. The signal transducers and activators of transcription factors upregulate the prosurvival Bcl-2 and Bcl-xL proteins in the majority of cases. The transcriptional targets of the nuclear factor-kappa B transcription factor in survival remain poorly characterized. These pathways are activated by the majority of FTKs in which they have been studied with some exceptions as detailed in the text. PI-3 kinase appears to be consistently upregulated by the FTKs, although the mechanism of activation may vary. The phosphorylation of Forkhead (FKHD) transcription factors and the p27Kip1 cell cycle inhibitor by Akt relegates them to the cytoplasm where they are inactive. FKHD can then no longer induce transcription of p27Kip1, whereas activator protein 1 transcription factors are transcribed in response to active mitogen-activated protein kinase pathways. These pathways are activated by the majority of FTKs in which they have been studied with some exceptions as detailed in the text.

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FTK-regulated mitogenic pathways in transformation

A sine qua non of the transformed state is that the normal constraints on cell cycle regulation are subverted, promoting unrestricted mitogenesis. But for an FTK this leaves open important questions: does the kinase promote cell cycle progression in primary cells upon its first expression and hence cause replicative stress?47, 48 or does it only subvert the cell cycle in collaboration with other oncogenes that become dysregulated following an initial wave of DNA damage? And, if that is the case, most important of all from a clinical perspective, does the activity and/or expression of the FTK remain critical for the maintenance of the transformed phenotype? In this section, we will focus on the first of these questions, although providing unambiguous answers is difficult due to our current lack of understanding of some of the signalling pathways that participate in FTK-mediated transformation.

A good example of this ambiguity is provided by recent findings on GAB-2, a scaffolding adaptor protein expressed ubiquitously in lymphoid cells, which was originally identified by its binding to the SHP-2 tyrosine phosphatase.49 Remarkably, bone marrow myeloid progenitors from Gab-2-/- mice are completely resistant to transformation by Bcr-Abl, pointing to a critical role for Gab-2 in its transforming actions, whereas transformation by the TEL-Jak2 FTK in the same system was only slightly reduced.50 The PI 3-kinase/AKT and extracellular signal-regulated kinase (ERK) signalling pathways were inhibited in the Gab-2-/- compared to wild-type cells, suggesting that these signals might be particularly important in transformation.50 Furthermore, the Bcr-Abl Y177F mutant was less efficient at transforming myeloid progenitors in this system than normal Bcr-Abl, consistent with the finding that Y177F mutants lose their leukaemogenic potential when expressed in transgenic mice.50, 51, 52 It is known that the Bcr-Abl Y177 site binds Grb-2, which in turn can couple the FTK to transforming pathways such as Shc/Ras/mitogen-activated protein (MAP) kinase.53 However, Bcr-Abl can also stimulate Ras by other mechanisms, at least in haematopoietic cell lines, so it is not yet certain which Y177-dependent signal is most important. GAB-2 is thought to mediate cytokine signalling in haematopoietic cells and it therefore seems a reasonable inference from present data to suggest that GAB-2 is important in mediating Bcr-Abl-induced mitogenesis, the FTK providing a persistent repertoire of signals that would, in the wild-type context, be provided in a regulated way via cytokine receptors.49

Consideration of the normal repertoire of cytokine-induced mitogenic signals provides further insights into the mechanisms whereby FTKs subvert the regulation of mitogenesis. It is well established that cytokines induce JAK-mediated activation of signal transducers and activators of transcription (STAT) proteins leading to the transcription of target genes associated with the regulation of cellular proliferation.54 Of the seven STAT family members, STATs 3 and 5 have been implicated in transformation following the expression of FTKs.52, 55, 56, 57, 58, 59, 60, 61 Interestingly, these same two STAT proteins are also activated in response to IL-2, IL-7, IL-9 and IL-15,54 consistent with the idea that FTKs can mimic aspects of cytokine-induced signalling. In fact, STAT5 is essential for the development of lymphoid malignancy following expression of either NPM-ALK52 or Tel-Jak262 in murine bone marrow transplanted into recipient mice. Furthermore, Tel-Jak2-mediated transformation is blocked following expression of SOCS-1, a negative regulator of Jak/STAT signalling that inhibits the actions of Jak2, so preventing phosphorylation and activation of both STATs 3 and 5,63 further highlighting the actions of these critical players in the transforming process. However, NPM-ALK transgenic mice when back-crossed to mice lacking STAT3 still developed T-cell malignancies even though STAT3 ablation could inhibit the transformation of murine embryonic fibroblasts.64 These data suggest some redundancy between the roles of STATs 3 and 5 in transformation, although STAT5 was not detected in the tumour tissues of NPM-ALK transgenic mice.49 Likewise, STAT5 is apparently not essential for Bcr-Abl-induced transformation, although there is evidence that it does play some role: thus transfection of STAT5-deficient cells with Bcr-Abl followed by transfer to irradiated mice still results in a myeloproliferative disorder, but this develops at a slower rate than in STAT5+ cells.65 The somewhat conflicting literature on the relative contributions of STAT3 and STAT5 to transformation no doubt reflect the variety of experimental models under investigation, but there is little doubt that STAT transcription factors per se are critical.

An important consequence of FTK-induced mitogenesis during the early stages of transformation may be replicative stress, leading to genomic instability and the consequent accumulation of mutations promoting cancer progression, as suggested by study of the pre-neoplastic lesions of a variety of cancers, including lung hyperplasia.47, 48 Nevertheless, the presence of cDNA encoding NPM-ALK and Bcr-Abl in healthy individuals suggests that expression of these proteins alone is necessary but not sufficient for the development of malignancy,66, 67 so replicative stress induced by mitogenesis is unlikely to be the only mechanism involved, pointing to a role for secondary mutations independent of FTK expression. In addition, some results point to a more direct role for the FTKs in promoting genomic instability, as discussed below.

Regulation of DNA repair and promotion of genomic instability

Some CML patients acquire a complex karyotype during disease evolution from the chronic phase to blast crisis, suggesting the continual emergence of new mutations and raising the question as to whether Bcr-Abl promotes genomic instability by mechanisms independent of replicative stress.68 In the context of primary transforming events, it is debatable whether the genetic abnormalities observed are a consequence or cause of transformation. Mice transgenic for the p190 form of Bcr-Abl develop karyotypic abnormalities in later stages of leukaemic development, suggesting that these are caused by the transformed state,69 but in the same mice, a 2–3-fold steady-state increase in the frequency of point mutations was observed in pre-leukaemic cells,70 pointing to a causal role for the fusion protein in promoting genetic instability. Further examination revealed an increased frequency of insertions and deletions in the precursor tissues.71 Both types of DNA damage could be partially prevented by administration of the c-Abl-specific inhibitor STI571.71, 72 These results are consistent with earlier cell line studies in which murine Ba/F3 cells were transfected with the p190 and p210 Bcr-Abl species leading to a 3–5-fold increase in the mutation frequency at two separate gene loci.73 Similarly, retroviral transduction of the p210 form of Bcr-Abl into 32D myeloid cells caused a rapid increase in chromosomal abnormalities.74, 75

It remains to be determined whether Bcr-Abl has direct effects on the DNA repair machinery or is itself a protein with mutagenic properties. The former hypothesis has been examined by Dierov et al.76 who showed that Bcr-Abl-inducible Ba/F3 cells respond to DNA damage by re-localization of the Bcr-Abl protein to the nucleus. Once in the nucleus, Bcr-Abl binds to the ataxia-telangiectasia and rad 3-related protein (ATR), blocking its actions in phosphorylating Chk1 and inducing the DNA repair process, resulting in a radio-resistant DNA synthesis phenotype.76 The idea that Bcr-Abl is more directly mutagenic is supported by experiments in which transfection of Bcr-Abl resulted in increased expression and activity of DNA polymerase beta, the most inaccurate of the mammalian DNA polymerases, thereby suggesting a possible mechanism for the mutator phenotype.73 This may be the cause of the 2–3-fold increase in the levels of point mutations observed in the transgenic mouse models already mentioned.72 It would therefore be of interest to examine the DNA repair processes following exposure of the p190 transgenic mice to point mutagens and clastogens.

Despite the results obtained using mouse models and cell lines, point mutations have not often been detected in CML cells, and common cytogenetic abnormalities are few, suggesting that a mutator phenotype may not be induced by Bcr-Abl in CML. Further work will be necessary to clarify whether these contrasting data represent genuine species differences, or perhaps simply the difficulties of obtaining human cells at the earliest stages of transformation.

FTK-mediated survival of DNA-damaged cells

Normally DNA-damaged cells die by apoptosis following induction of the p53 and related pathways, thereby eliminating those potentially lethal cells that are marked by genomic instability. But FTK-expressing cells subvert this process by triggering powerful survival signals that block DNA-damage-induced apoptosis (Figure 2). Much of the molecular analysis of the FTK-mediated survival signals has been performed using transformed cells and these data are discussed in the following section. However, once again mouse models are facilitating dissection of these pathways in pre-leukaemic primary cells, and we first briefly review these findings.

Transgenic mice expressing the p190 form of Bcr-Abl, in which pre-B cell leukaemias develop, provide useful models for investigation. B lineage cells normally undergo extensive apoptotic cell death as they develop in the mouse bone marrow. However, apoptosis is markedly reduced in bone marrow pre-B cells expressing Bcr-Abl, suggesting that the DNA-damage-induced response is suppressed.77 In addition, there is good evidence that Bcr-Abl reverses the apoptosis caused by cytokine deprivation and that this is relevant to the process of transformation in primary cells.78, 79 Early haematopoietic progenitors from normal mice undergo rapid apoptosis in the absence of cytokines, an event associated with upregulation of the proapoptotic protein Bim. However, in a mouse CML model in which Bcr-Abl is expressed under the control of the tec tyrosine kinase promoter, immature myeloid progenitors resist apoptosis upon cytokine withdrawal without the normal induction of Bim expression, effects that can be reversed by an Abl kinase inhibitor.79

In summary, it is a reasonable working model that FTKs exert their earliest transforming effects by inducing mitogenesis, causing replicative stress while subverting the normal processes of DNA repair and simultaneously inducing survival signals that prevent DNA-damage-triggered apoptosis and/or apoptosis arising from cytokine deprivation (Figure 2). The same, or parallel, survival signals may also promote the lineage progression of cells that might otherwise have died at critical stages of cytokine deprivation. The precise order of these events remains to be determined and to be confirmed in relevant models as a result of expression of the other FTKs.


FTK-induced signalling pathways in transformed cells

Much of the detailed biochemical analysis of FTK-induced signalling pathways has been carried out using cancer cell lines and, increasingly, primary tumour tissue from human or rodent. This has generated a large body of valuable data, reviewed below, and having particular relevance to clinical prognosis and therapeutic intervention. However, dysfunctional signalling pathways in cancer cells may, or may not, reproduce the initial FTK-induced events that caused transformation. In fact, in some cases it is clear that the biochemical signals measured in cancer cells are quite different, quantitatively and/or qualitatively, from those responsible for the initiation of transformation in pretumourigenic lineages.

Regulation of DNA repair

Fully transformed cells upregulate DNA repair mechanisms to promote survival, particularly in response to DNA-damaging agents used therapeutically. Details of the various pathways that mediate drug-resistance are not discussed here as they have been reviewed fully elsewhere.2, 80

The best defined action of the FTKs is to induce resistance to DNA-damaging compounds via upregulation of RAD51, an enzyme involved in rejoining of homologous ends. This involves dual transcriptional and post-translational control mechanisms, both mediated via STAT5, whereby the FTK increases RAD51 transcription as well as inducing increased RAD51 activity by direct phosphorylation of the enzyme.2, 80 This mechanism is common to all of the FTKs examined so far with the exception of Tel-TRKC which does not activate STAT5.80, 81 Cells transformed by Bcr-Abl also accumulate p53 in response to DNA damage, activating p21WAF-1 and GADD45, so inducing a delay in the G2 to M transition of the cell cycle.82 This delay is thought to allow time for DNA repair. In addition, the p210 isoform of Bcr-Abl has been reported to use an additional mechanism of DNA damage repair following genotoxic insult in which the fidelity of repair is affected. Thus, the CDC24 homology domain of Bcr retained in the p210 isoform binds the xeroderma pigmentosum B (XPB) protein, disabling its function.83 The helicase and ATPase activities of XPB in particular are affected and hence DNA repair by this mechanism is abrogated. It is this kind of mechanism which may underlie the genomic instability seen in the later blast crisis phase of the associated disease, consistent with the elevated level of reactive oxygen species (ROS) detected in Bcr-Abl-transformed cells,84, 85 an increase associated with double-strand breaks, transitions and transversions. Recently, the increase in ROS has been reported to be downstream of PI 3-kinase, which causes overactivity of the mitochondrial electron transport chain, thereby increasing glucose metabolism.85 Enhanced DNA damage combined with a lack of fidelity of repair mechanisms may contribute to the maintenance of the transformed phenotype and perhaps even progression to advanced disease status (e.g., blast crisis in the case of CML). Notably, such transformed cells are still able to escape apoptosis and survive with an unstable genome.

Survival and mitogenic pathways

FTK-transformed cells maintain their unrestricted growth by the continued activation of survival pathways that counteract the proapoptotic signals triggered by their own genomic DNA damage (Figure 3). For example, the Bcr-Abl kinase inhibitor STI571 causes apoptosis of the K562 cell line,86 thereby illustrating the phenomenon of oncogene addiction. It appears that even though the transformed cells have acquired multiple chromosomal aberrations, which might have been expected to generate alternative antiapoptotic mechanisms, in the few cases studied so far the cancer cells remain dependent on the FTK for survival. As a consequence, point mutations in the ATP binding pocket of the Bcr-Abl kinase enables escape of leukaemic cells from Gleevec-mediated kinase activity inhibition.87 Survival and mitogenic signals driven by the kinase are therefore essential for continued cell growth. Elucidation of both types of signalling pathway is critical in the design of new therapeutic strategies, and since the same molecules are often implicated in both types of pathway, they are discussed together below in the context of the key players involved:

The phosphoinositide 3-kinase family

The signalosomes formed by the Bcr-Abl, NPM-ALK, Tel-Jak2, Tel-TRKC (fibrosarcoma variant) and Tel-PDGFRbetaR FTKs include PI 3-kinase, which binds via an SH2 domain within its p85 subunit, resulting in the phosphorylation and activation of the ser/thr kinase protein kinase B (PKB/Akt).81, 88, 89, 90, 91, 92, 93, 94 The binding sites of PI 3-kinase to the FTKs have been identified and the bridging proteins Cbl, Shc and Gab-2 are involved.95 Once activated, Akt phosphorylates a plethora of downstream targets altering their activation status. The antiapoptotic functions of PI 3-kinase-mediated pathways have received particular attention (Figure 3). For example, PI 3-kinase mediates the phosphorylation and hence inactivation of the proapoptotic protein Bad, as demonstrated in NPM-ALK-transformed cells.88 Phosphorylated Bad is sequestered by 14-3-3 proteins in the cytoplasm, thereby downregulating its proapoptotic effects. PI 3-kinase activation also leads to upregulation of the Bcl-2 family members, including Bcl-2 itself,90, 96 although this does not appear to be the case in NPM-ALK-expressing cells, despite the expression of active PI 3-kinase.97

In addition to its role in mediating survival signals, it is also clear that FTK signalosome-associated PI 3-kinase is involved in regulating mitogenesis (Figure 3). For example, PI 3-kinase activation results in the phosphorylation of p27kip1 relegating it to the cytoplasm where it cannot exert its negative effects on cell-cycle-dependent kinase 2 (CDK2), which regulates entry into the S phase of the cell cycle.98 Using Ba/F3 and 32D cell lines as model systems, it has been shown that Tel-PDGFbetaR, NPM-ALK and Bcr-Abl expression results in inhibition of p27kip1 as a result of PI 3-kinase activation.94, 99, 100 These effects are most likely mediated by Forkhead transcription factors that are activated by Akt downstream of PI 3-kinase, thereby inhibiting the transcription of p27kip1.100, 101

STAT transcription factors

As discussed above in the context of transforming events, FTKs activate the STAT transcription factors, in some cases via Jak phosphorylation and activation and in others by direct phosphorylation.59, 60, 63, 102, 103 STATs 3 and 5 are phosphorylated as a result of NPM-ALK, Bcr-Abl and Tel-Jak2 expression49, 52, 59, 61, 62, 63, 64, 65, 103, 104, 105, 106, 107 (Figure 3). However, active STAT5 could only be seen in NPM-ALK-transformed cells following preincubation with the tyrosine phosphatase inhibitor sodium orthovanadate, suggesting that STAT5 dephosphorylation is a rapid event in these cells, whereas STAT3 was consistently phosphorylated in the absence of such phosphatase inhibitors.52 In addition, the p210 and p190 isoforms of Bcr-Abl activate STAT1 and the p190 isoform activates STAT6.103 Importantly, STAT 5 initiates the transcription of the antiapoptotic protein Bcl-xL in FTK-transformed cells.104, 108 Bcl-2 family proteins such as Bcl-xL sequester proapoptotic BH3-only proteins such as Bim and PUMA, maintaining mitochondrial membrane integrity, preventing release of cytochrome c and activation of the caspase execution cascade.

The nuclear factor-kappa B transcription factor

FTK-mediated signals commonly activate the nuclear factor-kappa B (NF-kappaB) transcription factor (Figure 3). In an inactive state, NF-kappaB is sequestered in the cytoplasm, bound to IkappaB proteins, which are ubiquitinated and subsequently degraded following phosphorylation, releasing NF-kappaB and promoting its translocation to the nucleus.109 Inhibition of NF-kappaB activity in Tel-PDGFbetaR and Tel-Jak2-transformed cells results in the induction of apoptotic cell death,110, 111 indicating a prosurvival role for NF-kappaB and consistent with the NF-kappaB activation observed in Bcr-Abl-transformed cells.111, 112 Antisense oligos against the predominant p65 subunit (RelA) prevented IL3 independence in these cells, suggesting a role for NF-kappaB in the panoply of signals whereby Bcr-Abl mediates cell growth and survival.112 Conversely, NF-kappaB is apparently not active in NPM-ALK-expressing patient-derived cell lines, even though the TNFR superfamily member CD30, usually associated with NF-kappaB activation, is expressed on the surface of these cells.113 Normally, the recruitment of TRAF proteins to CD30 (as in Hodgkin's Reed–Sternberg cells) leads to NF-kappaB activation, but in NPM-ALK positive cells this is blocked by an NPM-dependent mechanism, thereby preventing stimulation of the NF-kappaB pathway.113 However, p50 homodimers do form and these are associated with Bcl3 activity, a protein thought to be involved in protection from apoptosis114, 115

MAP/SAP kinase pathway

The FTKs contain binding sites for the adaptor proteins Grb-263, 116, 117 and Shc,81, 117, 118 generally associated with binding the exchange factor Sos, thereby activating Ras and downstream MAP kinase pathways.119 The ERK MAP kinase pathway is often associated with mitogenic signalling, whereas the stress-activated JNK and p38 SAP-kinase pathways have been implicated in apoptotic end points, although more recent data suggest additional roles in tumour cell proliferation.120 Thus, activation of all three MAP kinase pathways, ERK, JNK and p38, has been noted in Bcr-Abl-transformed haemopoietic progenitor cells121 and ERK MAP kinase is active in Tel-Jak2 and Tel-TRKC-transformed cells.81, 113, 122 In addition, Tel-PDGFbetaR-transformed Ba/F3 cells contain active JNK123 and all three MAP kinase pathways are active in the tumour tissues of NPM-ALK transgenic mice.49, 124 On the other hand, the ERK, JNK and p38 kinase pathways appear not to be activated in NPM-ALK-expressing human ALCL cell lines115 and likewise no ERK activation was detectable in Bcr-Abl-transformed Ba/F3 cell lines125 or Tel-PDGFbetaR-transformed 32D or Ba/F3 cells.126 The disparities in these data may reflect genuine differences in the signals induced by different FTKs; in addition, it seems likely that the disparate results reflect variations in the materials under investigation. Transformed cell lines are often not completely representative of the primary cancers as they are produced from patients who are generally in advanced stages of disease. These lines are then selected for growth in vitro, in this context perhaps rendering them independent of the MAP kinase pathways for activation of downstream transcription factors. The contradictory data in the literature on the role of the MAP kinase pathways in FTK-transformed cells therefore require further elucidation using murine models or transformed primary cells more representative of the cancer cell phenotype.

Activator protein 1 transcription factors

The three MAP kinase pathways induce a wide range of transcription factors implicated in mitogenic regulation, such as those which bind to the CRE, TRE and SRE response elements found within cytokine promoter regions. The combinatorial actions of the MAP/SAP kinase pathways are thereby integrated at this level of transcription factor regulation. For example, the activator protein 1 (AP-1) components fos and c-jun are active in Bcr-Abl;127 c-jun, JunB and Fra-2 in NPM-ALK;113, 115, 123 and c-jun in Tel-PDGFbetaR-transformed cells.123 Conversely, neither c-jun or c-fos were detected in Tel-Jak2-transformed BaF3 cells.105 The AP-1 components form heterodimers which bind to TPA response elements and induce transcription of proteins usually associated with a proliferative response.128



The literature describing transforming pathways induced by FTKs in primary cells is relatively sparse at present and is mainly based on studies investigating the actions of Bcr-Abl. However, initial studies have shown that FTKs may be involved in the induction of mitogenesis with, presumably, its associated replicative stress, and are certainly involved in preventing the elimination of DNA-damaged cells. The net outcome is the acquisition of genomic instability, coupled with inhibition of DNA repair and potentially error-prone DNA repair, promoting the next stages in the transforming process and, in the case of CML, progression to blast crisis.

Once transformation has occurred, a number of FTK-driven signalling pathways maintain cell proliferation and growth, generating the phenomenon of 'oncogene addiction'. FTK signalosomes couple directly to survival and mitogenic signalling pathways that involve PI 3-kinase, MAP/SAP kinase pathways and STAT, AP-1 and NF-kappaB transcription factors, although the precise composition of this repertoire of signalling molecules does vary somewhat depending on the FTK. Whether in the end the differences will out-number the similarities remains to be seen, but with the available data it is the commonalities between the FTK-induced signalling pathways that impress.

Our increasing understanding of the FTK signalling pathways does provide important insights into the potential therapeutic use of inhibitor compounds. The success of the Bcr-Abl inhibitor, STI571, has set a precedent for the use of kinase inhibitors in the treatment of those cancers expressing hyperactive kinases. However, relapses associated with the emergence of mutant forms of Bcr-Abl resistant to therapy highlight the need for additional therapies. The data presented in this review point to the importance of combination therapies targeting not only the FTK but, in addition, common FTK-stimulated signals, in particular the PI 3-kinase and MAP kinase pathways.

Research into FTKs has reached an exciting phase of development. Most of the work carried out so far has focused on the well-known Bcr-Abl kinase, but with the discovery of new hyperactive fusion kinases and the development of better models, further rapid progress is expected in understanding the molecular actions of FTKs in tumorigenesis and cancer progression.



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We thank the Leukaemia Research Fund, the Leukaemia and Lymphoma Society, and the British Biological Sciences Research Council for their financial support, and also apologise to those authors whose work has not been cited due to space constraints. SDT is supported by funding from the Leukaemia Research Fund (UK) and DRA from the Biotechnology and Biological Sciences Research Council.