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FOXM1 is a therapeutic target for high-risk multiple myeloma. Leukemia 2016 Apr;30(4):873-82

Date

12/10/2015

Pubmed ID

26648534

Pubmed Central ID

PMC4826574

DOI

10.1038/leu.2015.334

Abstract

The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM data sets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive upregulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin-dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was coregulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these three genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1(High) subset of myeloma.

Author List

Gu C, Yang Y, Sompallae R, Xu H, Tompkins VS, Holman C, Hose D, Goldschmidt H, Tricot G, Zhan F, Janz S

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Blotting, Western
Cell Proliferation
Forkhead Box Protein M1
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Immunoenzyme Techniques
Immunoprecipitation
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma
Neoplasm Staging
Prognosis
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75