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

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

doi:10.3390/cancers11081119

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.

Highlights

Forkhead box M1 (FOXM1) is a member of the Forkhead (FOX) family of transcription factors, which all share a highly conserved winged-helix DNA-binding domain [1]
NPM-anaplastic lymphoma kinase (ALK) + ALCL cell lines were assessed for expression of Forkhead Box M1 (FOXM1) by using a Western blot
Cell lysates harvested from peripheral blood mononuclear cells (PBMC) from a healthy individual showed no detectable FOXM1

Summary

Introduction

Forkhead box M1 (FOXM1) is a member of the Forkhead (FOX) family of transcription factors, which all share a highly conserved winged-helix DNA-binding domain [1]. Few published studies have addressed the functional importance of FOXM1 in hematologic cancers. These include precursor B-cell acute lymphoblastic leukemia [5], T-cell acute lymphoblastic leukemia [6,7], plasma cell myeloma [8], diffuse large B cell lymphoma [9], and acute myeloid leukemia [10]. In these studies, experimental results from FOXM1 knockout mice and in vitro studies in which FOXM1 was inhibited by a using pharmacologic agent (i.e., thiostrepton) or gene knockdown support the concept that FOXM1 contributes to the oncogenicity of these cancers. The mechanism by which FOXM1 mediates its oncogenic effects in these cancers is not well-understood

Methods

Results

Conclusion