Review

Leukemia (2005) 19, 1128–1134. doi:10.1038/sj.leu.2403797 Published online 19 May 2005

What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

S D Turner1 and D R Alexander1

1Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK

Correspondence: Dr SD Turner, LLSD, The Babraham Institute, Babraham Hall, Babraham Research Campus, Cambridge CB2 4AT, UK. Fax: +44 (0)1223 496023; E-mails: Suzanne.Turner@bbsrc.ac.uk, Denis.Alexander@BBSRC.AC.UK

Received 1 March 2005; Accepted 11 April 2005; Published online 19 May 2005.

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Abstract

The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is generated as a t(2;5) chromosomal breakpoint product, typically in CD30+ anaplastic large cell lymphomas. Activation of the NPM-ALK tyrosine kinase by NPM dimerisation causes autophosphorylation at multiple tyrosine residues and the consequent recruitment of a 'signalosome' that couples the fusion protein to pathways regulating mitogenesis and apoptosis. This review focuses on recent advances in our understanding of the transforming signals induced by this fusion protein in mouse models.

Keywords:

NPM-ALK, ALCL, oncogene, kinase

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Introduction

The fusion protein oncogenic tyrosine kinases (FOTKs) generated by non-reciprocal chromosomal translocations have been the focus of intensive recent investigation since they provide clearly defined model systems in which the molecular processes leading to transformation can be dissected in a systematic and rational manner. Although in many ways Bcr-Abl has provided the paradigmatic example for such studies, more recent investigations have included a wide range of FOTKs, in particular the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that is associated with anaplastic large cell lymphoma (ALCL). This review will focus on the development of mouse models and their contribution to our understanding of the oncogenic actions of NPM-ALK.

Several excellent reviews are available on the earlier NPM-ALK literature.1, 2, 3, 4 In brief, the first histological report of CD30 (ki-1)-positive ALCL was made by Stein et al.5 The disease was described as a pleiomorphic, large non-Hodgkin's lymphoma with sinus infiltration and anaplastic morphology. Involvement of a t(2;5) translocation with some cases of this disease was then reported by a number of groups, following which the breakpoint was cloned in 1994 by Morris and co-workers and simultaneously by Shiota et al.6, 7, 8, 9, 10 The cloning revealed a fusion protein comprising nucleophosmin (NPM) and a novel kinase with 64% identity to leucocyte tyrosine kinase, named anaplastic lymphoma kinase (ALK) after the disease with which it was first associated.8, 11 NPM-ALK consists of the N-terminal region of NPM fused to the entire intracellular portion of ALK (Figure 1). The resultant protein is a hyperactive tyrosine kinase with aberrant expression in haematopoietic cells. At least 10 ALK fusion partners besides NPM have been described in human tumours, mostly found in ALCL cases, and also including immunomyofibroblastic tumours.2 Typically 42% of ALK+ ALCL tumours derive from the T-lineage, 44% are of a 'null' phenotype, meaning that their lineage origins are not well characterised, and 14% are of a B-cell phenotype.12 A subtype of large B-cell lymphoma expressing the full-length ALK kinase and lacking the 2;5 translocation has also been described.13 In addition, CD30-negative diffuse large B-cell lymphomas expressing either NPM-ALK14, 15, 16 or a variant clatherin-like polypeptide chain-ALK fusion protein have been reported.17, 18 Therefore, there is considerable heterogeneity in the human tumours caused by inappropriate expression of hyperactive ALK, and this is reflected also in the mouse tumour models that have been developed.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

The NPM-ALK signalosome. The fusion protein contains 21 putative phosphorylation sites, only some of which have been characterised for ligand binding. The ensemble of signalling proteins (the 'signalosome') recruited to the fusion protein is responsible for coupling NPM-ALK to multiple signalling pathways. Note that the fusion protein is not to scale. Endogenous NPM binds to the fusion protein NPM, an interaction that may be important for the oncogenic actions of NPM-ALK.

Full figure and legend (59K)

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Mouse models of NPM-ALK-induced lymphoma

An ideal mouse cancer model will closely mimic the human phenotype(s), enable molecular analysis of early transforming events in a well-defined lineage, and utilise conditional lineage-specific promoters to facilitate expression and silencing of the transgene. This ideal has not yet been achieved for NPM-ALK, but some significant recent advances have been made in generating murine models, summarised in Table 1.


Transgenic mouse models

The choice of promoter for expressing the NPM-ALK transgene is problematic. NPM-ALK in ALCL cells is expressed from the endogenous NPM promoter, but this promoter is ubiquitously expressed, limiting its use in transgenic mice. The use of the ubiquitously expressed Bcr-promoter to generate Bcr-Abl transgenic mice resulted in embryonic lethality.25 Two groups have published lineage-restricted transgenic models, the first a transgenic mouse line in which NPM-ALK is expressed under the regulation of the CD4-promoter, expected to drive expression in the T-cell lineage,22 and the second in which expression is regulated by the haematopoietic cell-specific Vav-promoter.23 Line N16 of the CD4-promoter transgenic mice is of particular interest in that >90% of the tumours that developed were of a CD30+ T-cell phenotype. Intriguingly, however, the CD4-promoter also gave rise to tumours of a plasma cell phenotype, particularly in line N1, suggesting 'leakiness' of the promoter in the transgenic context, although the existence of a small, as yet unidentified, population of CD4+ B cells or B-cell precursors cannot yet be formally excluded. CD4 expression has infact been noted in clinical cases of B-cell ALK+ lymphoma, perhaps suggesting transformation of a CD4-expressing B-cell subset or, more likely, aberrant CD4 upregulation.13 In support of the latter interpretation, the plasmacytomas that developed in the CD4-promoter mouse model expressed the NPM-ALK protein, yet expression in pretumorigenic B220+ B cells was not detectable. Transgenic mice expressing the NPM-ALK transgene under the regulation of the T-cell-specific CD2-promoter also develop a B lymphoid malignancy, in some cases a diffuse large B-cell lymphoma and in others a histiocyte/T-cell-rich B-cell lymphoma (SD Turner, H Merz and DR Alexander, unpublished). NPM-ALK protein is likewise undetectable in pretumorigenic tissues in this context. In addition, NPM-ALK transgenic mice generated using the Vav-promoter also gave rise to tumours of a B-cell phenotype, plasmacytomas in the higher copy-number mouse line and putative peritoneal B1-cell tumours in the lower copy-number mice.23 The Vav-promoter normally gives rise to expression in all lineages of the haematopoietic compartment,26 suggesting that NPM-ALK preferentially transforms the B lineage in mice, in contrast to the T-lineage tumours that are more typical of human ALK+ ALCL.12 The fact that NPM-ALK expressing plasmacytomas have occasionally been reported in patients14, 15, 16 suggests that most transgenic mouse models generated so far mimic a rather rare human tumour entity.

Why would specific haematopoietic lineage promoters not generate NPM-ALK mouse models more closely mimicking human ALCL? There are a number of reasons why this may be so which might also shed light on the development of the human disease: for example, in mice, the translocation is not created de novo and endogenous NPM is still produced at normal levels, whereas the loss of one NPM allele as a result of the t(2;5) translocation may be important in the human context. For example, NPM binds to the tumour suppressor p53, regulating its stability and activity by a mechanism involving the human MDM2 (HMDM2) protein.27 Following exposure of cells to UV irradiation, NPM translocates from the nucleoli to the nucleoplasm, where it binds both p53 and HMDM2, preventing HMDM2-mediated p53 degradation.28 Loss of an NPM allele as a result of the t(2;5) translocation could therefore promote p53 degradation, preventing its proapoptotic and cell-cycle inhibitory actions following DNA damage, contributing to NPM-ALK-mediated oncogenesis. In addition, NPM-ALK impedes CD30 signalling and NFkappaB activation by a mechanism dependent on interaction between the N-terminal NPM domain of NPM-ALK with endogenous NPM.29 It is therefore possible that a 50% reduction in endogenous NPM expression might subvert this process. If either of these roles for endogenous NPM proves to be important in the transforming process, or in determining the phenotype of the transformed lineage, then possible oncogenic roles for other ALK fusion partners may need to be considered.

Transgenic mouse models are also beginning to provide useful information about the role of possible secondary events in the development of NPM-ALK-mediated neoplasia. The fact that the t(2;5) translocation has been detected in the lymphocytes of healthy individuals suggests that secondary events are critical for disease progression,30, 31, 32 consistent with the relatively long disease latency (13–38 weeks) in the CD4- and Vav-promoter transgenic NPM-ALK mouse lines. For example, regulation of IL-9 expression has been implicated in NPM-ALK-mediated disease progression based on an interesting mouse system developed by Lange et al.21 IL-9 expression has been noted in some cases of ALCL and its expression in transgenic mice results in the development of T cell tumours with a phenotype similar to ALCL but with a long latency.33 IL-9 is a multifunctional cytokine produced by activated T cells of T-Helper Type-2 (TH2) phenotype and is also involved in mast cell proliferation and differentiation.34 Lange et al hypothesised that IL-9 overexpression, together with NPM-ALK expression, might contribute to the development of ALK+ ALCL. Expression of NPM-ALK in IL-9 transgenic mouse bone marrow by retroviral transduction followed by implantation of the transduced bone marrow into IL-9 transgenic mice resulted in tumours of variable phenotypes.21 In some cases, T lymphoblastic lymphomas (46%) were observed and in others plasmacytomas (46%) or plasmablastic lymphomas (33%), similar to the heterogeneous range of human tumours expressing ALK. It is therefore possible that differentiation of T cells to the TH2 phenotype, or secondary mutations that elevate IL-9 by other mechanisms, might contribute to NPM-ALK-induced oncogenesis.

Chimaeric mouse models

In addition to transgenic mice, chimaeric mouse models have been developed whereby bone marrow is transduced ex vivo with a retroviral vector carrying the NPM-ALK cDNA, which is subsequently transplanted into lethally irradiated mice via tail vein injection. The first publication describing such a model reported a limited number of mice that developed tumours of a B-cell phenotype with plasmacytoid features.19 In this case the retroviral titre was low, supporting the idea that the 'default' phenotype of low NPM-ALK expression in mice involves transformation of the B lineage, consistent with the phenotype of the Vav-promoter NPM-ALK transgenic lines.23 Likewise Miething et al20 noted a difference in NPM-ALK+ tumour phenotypes according to differing multiplicity of infection (MOI). Mice receiving bone marrow infected with the higher MOI developed plasmacytomas, whereas those with the lower MOI, a histiocyte-rich lymphoma. Overall, therefore, higher levels of NPM-ALK expression in the murine context result in plasmacytomas and lower levels in B-cell lymphomas of less-well-defined phenotype. It would be of interest to determine whether NPM-ALK expression levels also differ in clinical cases of B- vs T-cell ALK+ lymphomas.

More recently a refined method for generating chimaeric mice that develop T-cell lymphomas has been reported. The model is generated by transducing the bone marrow cells of mice expressing the Cre recombinase from either the myeloid-specific lysoszyme-M or the granzyme-B promoter, which is mainly active in T cells. The retroviral vector incorporates a translational stop-cassette flanked by loxP recombination sites which recognise the Cre recombinase. Transduction of the promoter-specific Cre bone marrow with the NPM-ALK-loxP vector resulted in lineage-specific expression of the transgene. The lysozyme-M promoter gave rise to a histiocytic malignancy and the granzyme B promoter a mixed T-NHL/histiocyctic phenotype disease.35 These results are similar to those observed using the Vav-, CD2- or CD4-promoters to generate transgenic mouse models. The data also highlight the importance of both the level of NPM-ALK expression, as well as the promoter from which it is expressed, in determining the oncogenic outcome.

The mouse models described above, although not precisely mimicking NPM-ALK-expressing ALCL in humans, do provide a setting in which to examine the oncogenic events which promote tumour development and maintenance in a whole body context. In particular, they have enabled an examination of the signalling activities in tumour tissues and in most cases these data confirm those elucidated using cell lines generated from ALCL patients.

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NPM-ALK-induced signalling pathways

NPM-ALK, like other FOTKs, induces oncogenic signals by autophosphorylation at multiple Tyr residues, followed by recruitment of a signalosome: an ensemble of proteins containing docking SH2 or PTB domains that couples the fusion protein to downstream signalling pathways. Investigations based largely on cell line data suggest that the NPM-ALK signalosome stimulates pathways regulating mitogenesis and survival, involving the phosphoinositide 3-kinase (PI 3-kinase) and Ras/MAP kinase pathways, and the STAT family of transcription factors.36, 37, 38, 39, 40, 41, 42, 43 Here we focus on the contribution of mouse models to our understanding of these signals in situ.

There are 21 putative tyrosine autophosphorylation sites within the ALK domain, only some of which have been characterised,2 and a recent report suggests that as many as 46 different proteins selectively associate with NPM-ALK.44 Therefore, the signalosome may be considerably more complex than originally envisaged. As Figure 1 illustrates, NPM-ALK binds phospholipase-Citalic gamma (PLCitalic gamma) via an interaction at tyrosine residue 664, Shc via tyrosine 567, IRS-1 via tyrosine 156 and the src tyrosine kinase via tyrosine 418.45, 46, 47, 48 In addition, the Janus kinase (Jak2) binds to the region encoded by aa 118–138 of NPM-ALK and the TRAF2 protein to aa 394—397.29 NPM-ALK also forms a complex with Grb2 and PI 3-kinase, although no single site is responsible for this interaction, suggesting either the involvement of multiple docking sites or a role for adaptor molecules.22, 36, 47 More recently, a novel protein called Nuclear Interacting Partner of ALK (NIPA) was described which also forms part of the NPM-ALK signalosome.49 Similar complexes to those illustrated in Figure 1 have also been detected in primary cells from NPM-ALK transgenic mice, in particular the docking of Shc, IRS-1, Grb-2 and PI 3-kinase.22, 23 The development of further mouse models expressing mutant forms of the NPM-ALK protein might elucidate the role of these proteins in NPM-ALK-mediated lymphomagenesis in situ, although the identification of up to 46 proteins in the NPM-ALK signalosome suggests roles for multiple adaptors competing for binding to the same phosphotyrosine residue, so point mutations of single residues will not necessarily delineate single signalling pathways.44

The transforming signals initiated by NPM-ALK based on biochemical and cell line data are reviewed elsewhere4 and are summarised in Figure 2: we here compare and contrast these earlier findings with those obtained using mouse models.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

NPM-ALK-mediated signalling pathways regulating cell survival and proliferation.

Full figure and legend (94K)

The Ras/MAP kinase pathways and AP-1

The recruitment of Grb-2 and Shc to the NPM-ALK signalosome, as shown in both cell lines and transgenic mice,22, 23, 44, 45 is expected to stimulate guanine nucleotide exchange factors such as Sos, thereby activating the Ras-MAP Kinase pathway.50 Consistent with hyperactivation of the Ras pathway, phosphorylated ERK (pErk, the activated form of the kinase) has been detected in tumour cells derived from NPM-ALK transgenic mice,22, 23 confirming data generated in Drosophila and cell lines.41, 44, 51, 52, 53 The stress-activated JNK MAP Kinase pathway is also active in the tumour tissues of NPM-ALK transgenic mice.23 Whereas in some cellular contexts stress-induced JNK activation appears to mediate apoptosis, in tumour cells JNK can signal cell survival.54

Activation of the ERK and JNK MAP kinase pathways should promote the actions of downstream transcription factors such as the activator protein-1 family (AP-1). The AP-1 family is a group of dimeric basic region leucine zipper proteins consisting of hetero- or homodimers of Jun, Fos, Maf and ATF family members that recognise CRE or TPA response elements and initiate transcription of growth-promoting proteins and regulators of apoptosis.55 The ALK+ ALCL cell line Karpas-299 has been reported to express high levels of c-jun, Jun-B and Fra-2 proteins and hence displays AP-1-mediated transcriptional activity.38 These data have been confirmed in mouse models. Fra-2, c-jun, JunB and JunD proteins are present in the nuclear fractions of tumour cell lysates from NPM-ALK transgenic mice (SD Turner and DR Alexander, unpublished results). The regulation of AP-1 in response to NPM-ALK signalling needs to be examined further, using a wider range of human ALCL cell lines, human tumour samples and in the physiological setting provided by mouse models.

The Jak/STAT signalling pathways

Recently, the activated phosphorylated form of the STAT3 transcription factor has been detected in the majority (84%) of ALK+ ALCL tumour samples, as well as in the thymocytes and tumour tissues of NPM-ALK transgenic mice, and in cell lines.22, 42, 56, 57, 58 A striking and selective increase in both STAT3 and Jak-3 phosphorylation was noted in pretumorigenic thymocytes from CD4-promoter NPM-ALK transgenic mice consistent with a Jak-3-mediated phosphorylation of STAT3.22 However, activation of STAT5 was not seen in these mice as has been noted in cell line studies.22, 39

STAT3 activation appears to mediate both survival and proliferative signals via transcriptional activation of downstream targets, some of which have been identified (Figure 2). Survival signals resulting from STAT3 activation include upregulation of the antiapoptotic Bcl2, Bcl-xL, Mcl1 and survivin proteins, whereas proliferative signals are provided by positive regulators of G1 cell-cycle progression such as cyclin D3 and c-myc.56 Consistent with the STAT3 activation observed, cyclin D3 and c-myc expression are upregulated in tumour tissues from NPM-ALK transgenic mice.22 Expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) protein phosphorylation is another consequence of STAT3 activity in ALK+ ALCL cells and human ALK+ ALCL tumour tissues.59 TIMP-1 inhibits tumour spread and promotes cell survival in a STAT3-dependent manner.59 TIMP-1 activity may therefore inhibit tumour spread in ALK+ ALCL, perhaps the reason for a more favourable clinical outcome when STAT3 expression is observed.58 The status of the TIMP-1 protein is yet to be elucidated in the NPM-ALK mouse models as is the status of the RAD51 protein. RAD51 is activated in response to STAT5 in NPM-ALK-transformed cell lines and is responsible for the repair of DNA double-strand breaks contributing to the drug resistance of these cells.60

The PI 3-kinase pathway

As mentioned previously above, PI 3-kinase is one of the components of the NPM-ALK signalosome and this has also now been demonstrated in the haemopoietic tissues of NPM-ALK transgenic mice.22 Consistent with this observation, the Akt protein downstream of PI 3-kinase is active in NPM-ALK-transformed cells.36, 40 Upon binding to PI 3-kinase, NPM-ALK activates an antiapoptotic pathway by phosphorylating Bad, preventing its binding to Bcl-xL.36 The serine phosphorylated form of Bad is bound to 14-3-3 proteins in the cytoplasm preventing translocation to the mitochondrial membrane.61 Bcl-xL is then able to maintain mitochondrial membrane integrity by preventing release of cytochrome c and activation of apoptosis mediated by caspase 9, thereby inhibiting the caspase activation cascade that leads to apoptosis.

In addition to the antiapoptotic effects of PI 3-kinase signalling, the enzyme is also involved in mediating NPM-ALK-induced actions on regulation of the cell cycle. FOXO3a is a member of the Forkhead (FKHD) family of transcription factors that is regulated by Akt-induced phosphorylation at three sites, Thr32, Ser253, Ser315.62 When in an unphosphorylated form it can translocate to the nucleus and induce the transcription of proapoptotic and cell-cycle inhibitory proteins. In Ba/F3 cells, with either constitutive or inducible expression of NPM-ALK, FOXO3a is phosphorylated by Akt and hence as a consequence excluded from the nucleus, thereby promoting cell-cycle progression.63 The CDK-dependent inhibitor p27kip1 is also phosphorylated in response to Akt activation in NPM-ALK-expressing cells, targeting it for proteosomal degradation and so preventing cell-cycle arrest.64, 65 Therefore, PI 3-kinase appears to play a key role in mediating NPM-ALK-induced mitogenesis by acting on cell-cycle regulation via several distinct downstream pathways. Many of these molecular details have been elucidated using cell line systems, and it will be of interest to determine whether they can be reproduced using primary murine cells expressing NPM-ALK.

CD30 signalling pathways

CD30 is expressed on the surface of ALCL cells as it is on Reed-Sternberg cells (H/RS) of Hodgkin's lymphoma.5 Interestingly, introduction of NPM-ALK into H/RS cells causes the cells to develop a phenotype similar to ALK+ ALCL, suggesting that CD30 signalling plays a role in the development of the ALCL phenotype.29 The modulating effect of NPM-ALK on CD30-mediated signals provides a fascinating example of how an FOTK can shape the phenotype of cells during the oncogenic process. Development of a mouse model in which NPM-ALK expression is directed to CD30-expressing cells might therefore prove to be important in developing a disease model more closely mimicking ALK+ ALCL.

Concluding comments

NPM-ALK is an oncogenic tyrosine kinase, which acts as a docking protein for a signalosome which in turn couples the fusion protein to signalling pathways with mitogenic, antiapoptotic and possibly DNA repair capabilities. Much of the published work on NPM-ALK signalling has been carried out using cell line models that are useful for biochemical analysis but do not necessarily resemble the lineages in vivo in which NPM-ALK exerts its oncogenic actions. The analysis of NPM-ALK-mediated oncogenic events using mouse models is in its infancy, but is already beginning to complement data generated using cell lines. One obvious advantage of the mouse models is that the tumours develop in situ where the effects of the surrounding tissues, the contribution made by the immune system, the extracellular matrix and angiogenesis are all important factors. A mouse model that mimics NPM-ALK+ ALCL more closely would facilitate further investigation of the molecular actions of NPM-ALK in pretumourigenic lineages, and ideally would involve an inducible model in which both the transforming activity of the fusion protein as well as the transformed phenotype could be thoroughly elucidated.

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Acknowledgements

SDT is supported with funding from the Leukaemia Research Fund (UK) and the Leukemia and Lymphoma Society (USA) (6018-03). DRA is supported with funding from the Biotechnology and Biological Sciences Research Council.