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

doi:10.3390/cancers11081119

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 journal › Article › peer-review

5 Scopus citations

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 language	English (US)
Article number	1119
Journal	Cancers
Volume	11
Issue number	8
DOIs	https://doi.org/10.3390/cancers11081119
State	Published - Aug 2019

Keywords

Anaplastic large cell lymphoma
FOXM1
Gene regulation
NPM-ALK
Thiostrepton

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3390/cancers11081119

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@article{9c605d80bdcf423a8a557bf653fbadcb,

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

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.",

keywords = "Anaplastic large cell lymphoma, FOXM1, Gene regulation, NPM-ALK, Thiostrepton",

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",

note = "Funding Information: Acknowledgments: M.H. acknowledges the support of a Canada Graduate Scholarships-Master{\textquoteright}s Award. M.H. is an MSc. candidate at the University of Alberta. This work is submitted in partial fulfillment of the requirement for the J.L. acknowledges operating support China Scholarship Council scholarship. The authors thank Carlos Velazquez for sharing the biotinylated FOXM1 probe. Funding Information: M.H. acknowledges the support of a Canada Graduate Scholarships-Master?s Award. M.H. is an MSc. candidate at the University of Alberta. This work is submitted in partial fulfillment of the requirement for the J.L. acknowledges operating support China Scholarship Council scholarship. The authors thank Carlos Velazquez for sharing the biotinylated FOXM1 probe. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = aug,

doi = "10.3390/cancers11081119",

language = "English (US)",

volume = "11",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "8",

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T1 - Npm-alk is a key regulator of the oncoprotein foxm1 in alk-positive anaplastic large cell lymphoma

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

N1 - Funding Information: Acknowledgments: M.H. acknowledges the support of a Canada Graduate Scholarships-Master’s Award. M.H. is an MSc. candidate at the University of Alberta. This work is submitted in partial fulfillment of the requirement for the J.L. acknowledges operating support China Scholarship Council scholarship. The authors thank Carlos Velazquez for sharing the biotinylated FOXM1 probe. Funding Information: M.H. acknowledges the support of a Canada Graduate Scholarships-Master?s Award. M.H. is an MSc. candidate at the University of Alberta. This work is submitted in partial fulfillment of the requirement for the J.L. acknowledges operating support China Scholarship Council scholarship. The authors thank Carlos Velazquez for sharing the biotinylated FOXM1 probe. Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2019/8

Y1 - 2019/8

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.

KW - Anaplastic large cell lymphoma

KW - FOXM1

KW - Gene regulation

KW - NPM-ALK

KW - Thiostrepton

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U2 - 10.3390/cancers11081119

DO - 10.3390/cancers11081119

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SN - 2072-6694

VL - 11

JO - Cancers

JF - Cancers

IS - 8

M1 - 1119

ER -

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

Abstract

Keywords

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