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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

Sensitivity heat maps of the NPM-ALK network.Sensitivity maps were calculated in response to variations in JAK3/STAT3, SHP1 and NPM-ALK activities. Independent activity levels of JAK3/STAT3 and SHP1 are represented in the xy-plane, those of NPM-ALK are represented along the z-axis. Sensitivity of proliferation and cell survival calculated with respect to JAK3/STAT3 variations results in positive values (A and B, respectively). Values with respect to SHP1 variations, which only connects other network nodes by inhibiting links, are negative (C and D, respectively). The pink arrow in B highlights a region of increased sensitivity at high NPM-ALK activity. The sensitive areas in C and D (yellow) indicate a variable pattern of sensitive regions of the parameter space as a function of NPM-ALK activity. At intermediate NPM-ALK activity, these regions are larger than at low and high NPM-ALK activity. In addition, a bi-modal sensitivity pattern appears at high levels of NPM-ALK activity.
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pone.0163011.g004: Sensitivity heat maps of the NPM-ALK network.Sensitivity maps were calculated in response to variations in JAK3/STAT3, SHP1 and NPM-ALK activities. Independent activity levels of JAK3/STAT3 and SHP1 are represented in the xy-plane, those of NPM-ALK are represented along the z-axis. Sensitivity of proliferation and cell survival calculated with respect to JAK3/STAT3 variations results in positive values (A and B, respectively). Values with respect to SHP1 variations, which only connects other network nodes by inhibiting links, are negative (C and D, respectively). The pink arrow in B highlights a region of increased sensitivity at high NPM-ALK activity. The sensitive areas in C and D (yellow) indicate a variable pattern of sensitive regions of the parameter space as a function of NPM-ALK activity. At intermediate NPM-ALK activity, these regions are larger than at low and high NPM-ALK activity. In addition, a bi-modal sensitivity pattern appears at high levels of NPM-ALK activity.

Mentions: The effects of variations in JAK3/STAT3 activity on proliferation (i.e., the sensitivity of proliferation with respect to changes in JAK3/STAT3 independent activity) decrease with increasing NPM-ALK (yellow areas in Fig 4A). The larger the activity of NPM-ALK, the larger are the values of both JAK3/STAT3 and SHP1’s activities where high sensitivity is observed. If one considers activities of NPM-ALK in the range set by β = 0.1 to 10, it appears that proliferation is not very sensitive to variations in JAK3/STAT3 activity unless both SHP1 and JAK3/STAT3 are (very) highly active. In general, low activity of SHP1 indicates that proliferation does not depend on JAK3/STAT3, unless NPM-ALK levels are low as well.


Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy
Sensitivity heat maps of the NPM-ALK network.Sensitivity maps were calculated in response to variations in JAK3/STAT3, SHP1 and NPM-ALK activities. Independent activity levels of JAK3/STAT3 and SHP1 are represented in the xy-plane, those of NPM-ALK are represented along the z-axis. Sensitivity of proliferation and cell survival calculated with respect to JAK3/STAT3 variations results in positive values (A and B, respectively). Values with respect to SHP1 variations, which only connects other network nodes by inhibiting links, are negative (C and D, respectively). The pink arrow in B highlights a region of increased sensitivity at high NPM-ALK activity. The sensitive areas in C and D (yellow) indicate a variable pattern of sensitive regions of the parameter space as a function of NPM-ALK activity. At intermediate NPM-ALK activity, these regions are larger than at low and high NPM-ALK activity. In addition, a bi-modal sensitivity pattern appears at high levels of NPM-ALK activity.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036789&req=5

pone.0163011.g004: Sensitivity heat maps of the NPM-ALK network.Sensitivity maps were calculated in response to variations in JAK3/STAT3, SHP1 and NPM-ALK activities. Independent activity levels of JAK3/STAT3 and SHP1 are represented in the xy-plane, those of NPM-ALK are represented along the z-axis. Sensitivity of proliferation and cell survival calculated with respect to JAK3/STAT3 variations results in positive values (A and B, respectively). Values with respect to SHP1 variations, which only connects other network nodes by inhibiting links, are negative (C and D, respectively). The pink arrow in B highlights a region of increased sensitivity at high NPM-ALK activity. The sensitive areas in C and D (yellow) indicate a variable pattern of sensitive regions of the parameter space as a function of NPM-ALK activity. At intermediate NPM-ALK activity, these regions are larger than at low and high NPM-ALK activity. In addition, a bi-modal sensitivity pattern appears at high levels of NPM-ALK activity.
Mentions: The effects of variations in JAK3/STAT3 activity on proliferation (i.e., the sensitivity of proliferation with respect to changes in JAK3/STAT3 independent activity) decrease with increasing NPM-ALK (yellow areas in Fig 4A). The larger the activity of NPM-ALK, the larger are the values of both JAK3/STAT3 and SHP1’s activities where high sensitivity is observed. If one considers activities of NPM-ALK in the range set by β = 0.1 to 10, it appears that proliferation is not very sensitive to variations in JAK3/STAT3 activity unless both SHP1 and JAK3/STAT3 are (very) highly active. In general, low activity of SHP1 indicates that proliferation does not depend on JAK3/STAT3, unless NPM-ALK levels are low as well.

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