Npm-alk is a key regulator of the oncoprotein foxm1 in alk-positive anaplastic large cell lymphoma

Moinul Haque, Jing Li, Yung Hsing Huang, Meaad Almowaled, Carter J. Barger, Adam R. Karpf, Peng Wang, Will Chen, Suzanne D. Turner, Raymond Lai

Research output: Contribution to journalArticle

Abstract

Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.

Original languageEnglish (US)
Article number1119
JournalCancers
Volume11
Issue number8
DOIs
StatePublished - Aug 2019

Fingerprint

Anaplastic Large-Cell Lymphoma
Oncogene Proteins
Thiostrepton
Phosphorylation
Neoplasms
Cell Cycle Checkpoints
Small Interfering RNA
Transgenic Mice
Agar
Transcription Factors
Apoptosis
Cell Line
DNA
Growth
Proteins

Keywords

  • Anaplastic large cell lymphoma
  • FOXM1
  • Gene regulation
  • NPM-ALK
  • Thiostrepton

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Npm-alk is a key regulator of the oncoprotein foxm1 in alk-positive anaplastic large cell lymphoma. / Haque, Moinul; Li, Jing; Huang, Yung Hsing; Almowaled, Meaad; Barger, Carter J.; Karpf, Adam R.; Wang, Peng; Chen, Will; Turner, Suzanne D.; Lai, Raymond.

In: Cancers, Vol. 11, No. 8, 1119, 08.2019.

Research output: Contribution to journalArticle

Haque, M, Li, J, Huang, YH, Almowaled, M, Barger, CJ, Karpf, AR, Wang, P, Chen, W, Turner, SD & Lai, R 2019, 'Npm-alk is a key regulator of the oncoprotein foxm1 in alk-positive anaplastic large cell lymphoma', Cancers, vol. 11, no. 8, 1119. https://doi.org/10.3390/cancers11081119
Haque, Moinul ; Li, Jing ; Huang, Yung Hsing ; Almowaled, Meaad ; Barger, Carter J. ; Karpf, Adam R. ; Wang, Peng ; Chen, Will ; Turner, Suzanne D. ; Lai, Raymond. / Npm-alk is a key regulator of the oncoprotein foxm1 in alk-positive anaplastic large cell lymphoma. In: Cancers. 2019 ; Vol. 11, No. 8.
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abstract = "Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.",
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author = "Moinul Haque and Jing Li and Huang, {Yung Hsing} and Meaad Almowaled and Barger, {Carter J.} and Karpf, {Adam R.} and Peng Wang and Will Chen and Turner, {Suzanne D.} and Raymond Lai",
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AU - Haque, Moinul

AU - Li, Jing

AU - Huang, Yung Hsing

AU - Almowaled, Meaad

AU - Barger, Carter J.

AU - Karpf, Adam R.

AU - Wang, Peng

AU - Chen, Will

AU - Turner, Suzanne D.

AU - Lai, Raymond

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N2 - Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.

AB - Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.

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