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Cancers (Basel). 2019 Aug 6;11(8). pii: E1119. doi: 10.3390/cancers11081119.

NPM-ALK Is a Key Regulator of the Oncoprotein FOXM1 in ALK-Positive Anaplastic Large Cell Lymphoma.

Author information

1
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G2R3, Canada.
2
Electron Microscopy Center, Basic Medical Science College, Harbin Medical University, Harbin 150080, Heilongjiang, China.
3
Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
4
Department of Hematology, University of Alberta, Edmonton, AB T6G2R3, Canada.
5
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB20QQ, UK.
6
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G2R3, Canada. rlai@ualberta.ca.
7
Department of Oncology, University of Alberta, Edmonton, AB T6G2R3, Canada. rlai@ualberta.ca.

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:

FOXM1; NPM-ALK; anaplastic large cell lymphoma; gene regulation; thiostrepton

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