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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.


Related in: MedlinePlus

Signal flow in the NPM-ALK network.Network configurations that predispose NPM-ALK to optimally control proliferation (A) and cell survival (B) are depicted where the size of a node represents its effect on the endpoint—the smaller is the node, the smaller is the effect. The colour represents signal intensity—the darker the node, the more active it is when the control node is highly active.
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pone.0163011.g003: Signal flow in the NPM-ALK network.Network configurations that predispose NPM-ALK to optimally control proliferation (A) and cell survival (B) are depicted where the size of a node represents its effect on the endpoint—the smaller is the node, the smaller is the effect. The colour represents signal intensity—the darker the node, the more active it is when the control node is highly active.

Mentions: SHP1 has an inhibitory effect on proliferation and cell survival. Its effect in the simulations is however masked by the downstream control node (NPM-ALK), whose activity in the simulations is increased without influence from SHP1’s state. To further validate our results, we repeated the same analysis using SHP1 as control node. We identified the active nodes in the network following an independent activity increase of SHP1, and we obtained a comparable outcome as with NMP-ALK (compare Fig 3 with S1 Fig). This suggests that perturbations of central network components such as NPM-ALK or SHP1 result in the activation of the same signalling pathways.


Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy
Signal flow in the NPM-ALK network.Network configurations that predispose NPM-ALK to optimally control proliferation (A) and cell survival (B) are depicted where the size of a node represents its effect on the endpoint—the smaller is the node, the smaller is the effect. The colour represents signal intensity—the darker the node, the more active it is when the control node is highly active.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0163011.g003: Signal flow in the NPM-ALK network.Network configurations that predispose NPM-ALK to optimally control proliferation (A) and cell survival (B) are depicted where the size of a node represents its effect on the endpoint—the smaller is the node, the smaller is the effect. The colour represents signal intensity—the darker the node, the more active it is when the control node is highly active.
Mentions: SHP1 has an inhibitory effect on proliferation and cell survival. Its effect in the simulations is however masked by the downstream control node (NPM-ALK), whose activity in the simulations is increased without influence from SHP1’s state. To further validate our results, we repeated the same analysis using SHP1 as control node. We identified the active nodes in the network following an independent activity increase of SHP1, and we obtained a comparable outcome as with NMP-ALK (compare Fig 3 with S1 Fig). This suggests that perturbations of central network components such as NPM-ALK or SHP1 result in the activation of the same signalling pathways.

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.


Related in: MedlinePlus