title: FOXM1 is a therapeutic target for high-risk multiple myeloma.
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.
authors.affiliation: Basic Medical College, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.|Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Gu
authors.affiliation: Basic Medical College, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.|Department of Internal Medicine, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.|Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sompallae
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Tompkins
authors.affiliation: Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Holman
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Janz
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger