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Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

View Article: PubMed Central - PubMed

ABSTRACT

A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.

No MeSH data available.


NPM-ALK network scheme.Nodes and links in black represent the core network whose components have been considered in our simulations. The surrounding components (nodes and arrows represented with grey dotted lines) indicate factors that influence the core network in different contexts and are not considered in the simulations. In the core network, the relevance of different nodes for signalling in disease development are linked by activating and inhibiting network’s links, indicated with → and ⊣, respectively. “Interleukins” includes IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and IL-22 [34–36], while “Phosphatases” refers to lipid phosphatases such as the phosphatase and tensin homologue, which converts phosphatidylinositol-3,4,5-triphosphate (PIP3) back to phosphatidylinositol-4,5-bisphosphate (PIP2) [37].
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pone.0163011.g001: NPM-ALK network scheme.Nodes and links in black represent the core network whose components have been considered in our simulations. The surrounding components (nodes and arrows represented with grey dotted lines) indicate factors that influence the core network in different contexts and are not considered in the simulations. In the core network, the relevance of different nodes for signalling in disease development are linked by activating and inhibiting network’s links, indicated with → and ⊣, respectively. “Interleukins” includes IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and IL-22 [34–36], while “Phosphatases” refers to lipid phosphatases such as the phosphatase and tensin homologue, which converts phosphatidylinositol-3,4,5-triphosphate (PIP3) back to phosphatidylinositol-4,5-bisphosphate (PIP2) [37].

Mentions: The NPM-ALK network (Fig 1) was first investigated by simulating all combinations of network states where each node could adopt one of two initial activity states: high (β = 0.1) or low (β = 0.001) (see the “Methods” section for details). This model corresponds to tumours or cell lines where the activity of certain components in the signalling network becomes higher or lower due to external perturbations such as environmental factors or internal perturbations due to gene mutations or epigenetic alterations.


Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy
NPM-ALK network scheme.Nodes and links in black represent the core network whose components have been considered in our simulations. The surrounding components (nodes and arrows represented with grey dotted lines) indicate factors that influence the core network in different contexts and are not considered in the simulations. In the core network, the relevance of different nodes for signalling in disease development are linked by activating and inhibiting network’s links, indicated with → and ⊣, respectively. “Interleukins” includes IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and IL-22 [34–36], while “Phosphatases” refers to lipid phosphatases such as the phosphatase and tensin homologue, which converts phosphatidylinositol-3,4,5-triphosphate (PIP3) back to phosphatidylinositol-4,5-bisphosphate (PIP2) [37].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036789&req=5

pone.0163011.g001: NPM-ALK network scheme.Nodes and links in black represent the core network whose components have been considered in our simulations. The surrounding components (nodes and arrows represented with grey dotted lines) indicate factors that influence the core network in different contexts and are not considered in the simulations. In the core network, the relevance of different nodes for signalling in disease development are linked by activating and inhibiting network’s links, indicated with → and ⊣, respectively. “Interleukins” includes IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and IL-22 [34–36], while “Phosphatases” refers to lipid phosphatases such as the phosphatase and tensin homologue, which converts phosphatidylinositol-3,4,5-triphosphate (PIP3) back to phosphatidylinositol-4,5-bisphosphate (PIP2) [37].
Mentions: The NPM-ALK network (Fig 1) was first investigated by simulating all combinations of network states where each node could adopt one of two initial activity states: high (β = 0.1) or low (β = 0.001) (see the “Methods” section for details). This model corresponds to tumours or cell lines where the activity of certain components in the signalling network becomes higher or lower due to external perturbations such as environmental factors or internal perturbations due to gene mutations or epigenetic alterations.

View Article: PubMed Central - PubMed

ABSTRACT

A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.

No MeSH data available.