Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Multiple Myeloma, Gammopathies

FOXM1 is a therapeutic target for high-risk multiple myeloma

Leukemia volume 30, pages 873–882 (2016)Cite this article

Subjects

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 FOXM1High subset of myeloma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020–2028.

    Article  CAS  Google Scholar 

  2. Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.

    Article  CAS  Google Scholar 

  3. Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B et al. A gene expression signature for high-risk multiple myeloma. Leukemia 2012; 26: 2406–2413.

    Article  CAS  Google Scholar 

  4. Wu P, Walker BA, Broyl A, Kaiser M, Johnson DC, Kuiper R et al. A gene expression based predictor for high risk myeloma treated with intensive therapy and autologous stem cell rescue. Leuk Lymphoma 2015; 56: 594–601.

    Article  CAS  Google Scholar 

  5. Rajkumar SV . Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol 2012; 87: 78–88.

    Article  Google Scholar 

  6. Koo CY, Muir KW, Lam EW . FOXM1: from cancer initiation to progression and treatment. Biochim Biophys Acta 2012; 1819: 28–37.

    Article  CAS  Google Scholar 

  7. Gong A, Huang S . FoxM1 and Wnt/beta-catenin signaling in glioma stem cells. Cancer Res 2012; 72: 5658–5662.

    Article  CAS  Google Scholar 

  8. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008; 68: 190–197.

    Article  CAS  Google Scholar 

  9. Hajek R, Okubote SA, Svachova H . Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma. Br J Haematol 2013; 163: 551–564.

    Article  Google Scholar 

  10. Wonsey DR, Follettie MT . Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 2005; 65: 5181–5189.

    Article  CAS  Google Scholar 

  11. Laoukili J, Stahl M, Medema RH . FoxM1: at the crossroads of ageing and cancer. Biochim Biophys Acta 2007; 1775: 92–102.

    CAS  Google Scholar 

  12. Neri P, Bahlis NJ . Genomic instability in multiple myeloma: mechanisms and therapeutic implications. Expert Opin Biol Ther 2013; 13 (Suppl 1): S69–S82.

    Article  CAS  Google Scholar 

  13. Uddin S, Hussain AR, Ahmed M, Siddiqui K, Al-Dayel F, Bavi P et al. Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma. Haematologica 2012; 97: 1092–1100.

    Article  CAS  Google Scholar 

  14. Tompkins VS, Han SS, Olivier A, Syrbu S, Bair T, Button A et al. Identification of candidate B-lymphoma genes by cross-species gene expression profiling. PLoS One 2013; 8: e76889.

    Article  CAS  Google Scholar 

  15. Kong X, Li L, Li Z, Le X, Huang C, Jia Z et al. Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res 2013; 73: 3987–3996.

    Article  CAS  Google Scholar 

  16. Cai Y, Balli D, Ustiyan V, Fulford L, Hiller A, Misetic V et al. Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis. J Biol Chem 2013; 288: 22527–22541.

    Article  CAS  Google Scholar 

  17. Wang Z, Zheng Y, Park HJ, Li J, Carr JR, Chen YJ et al. Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther 2013; 12: 759–767.

    Article  CAS  Google Scholar 

  18. Motiwala T, Kutay H, Zanesi N, Frissora FW, Mo X, Muthusamy N et al. PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model. Leukemia 2015; 29: 1350–1359.

    Article  CAS  Google Scholar 

  19. Kopanja D, Pandey A, Kiefer M, Wang Z, Chandan N, Carr JR et al. Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol 2015; 63: 429–436.

    Article  CAS  Google Scholar 

  20. Zona S, Bella L, Burton MJ, Nestal de Moraes G, Lam EW . FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta 2014; 1839: 1316–1322.

    Article  CAS  Google Scholar 

  21. Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW et al. FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma. PLoS One 2012; 7: e34329.

    Article  CAS  Google Scholar 

  22. Eckers JC, Kalen AL, Sarsour EH, Tompkins VS, Janz S, Son JM et al. Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells. Radiat Res 2014; 182: 420–429.

    Article  Google Scholar 

  23. Karunarathna U, Kongsema M, Zona S, Gong C, Cabrera E, Gomes AR et al. OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance. Oncogene 2016; 35: 1433–1444.

    Article  CAS  Google Scholar 

  24. Hou Y, Li W, Sheng Y, Li L, Huang Y, Zhang Z et al. The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells. Nat Immunol 2015; 16: 810–818.

    Article  CAS  Google Scholar 

  25. Gong AH, Wei P, Zhang S, Yao J, Yuan Y, Zhou AD et al. FoxM1 drives a feed-forward STAT3-activation signaling loop that promotes the self-renewal and tumorigenicity of glioblastoma stem-like cells. Cancer Res 2015; 75: 2337–2348.

    Article  CAS  Google Scholar 

  26. Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC et al. FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget 2015; 6: 2349–2365.

    Google Scholar 

  27. Gormally MV, Dexheimer TS, Marsico G, Sanders DA, Lowe C, Matak-Vinkovic D et al. Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition. Nat Commun 2014; 5: 5165.

    Article  CAS  Google Scholar 

  28. Halasi M, Gartel AL . Targeting FOXM1 in cancer. Biochem Pharmacol 2013; 85: 644–652.

    Article  CAS  Google Scholar 

  29. Gazdar AF, Oie HK, Kirsch IR, Hollis GF . Establishment and characterization of a human plasma cell myeloma culture having a rearranged cellular myc proto-oncogene. Blood 1986; 67: 1542–1549.

    CAS  Google Scholar 

  30. Zhang XG, Gaillard JP, Robillard N, Lu ZY, Gu ZJ, Jourdan M et al. Reproducible obtaining of human myeloma cell lines as a model for tumor stem cell study in human multiple myeloma. Blood 1994; 83: 3654–3663.

    CAS  Google Scholar 

  31. Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS . Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 1999; 93: 3044–3052.

    CAS  Google Scholar 

  32. Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006; 66: 7661–7667.

    Article  CAS  Google Scholar 

  33. Lombardi L, Poretti G, Mattioli M, Fabris S, Agnelli L, Bicciato S et al. Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosomes Cancer 2007; 46: 226–238.

    Article  CAS  Google Scholar 

  34. Yellapantula V, Divya T, Dinu V, Scotch M . Informatics approaches for integrative analysis of disparate high-throughput genomic datasets in cander. Arizona State University (ASU) Electronic Dissertations and Theses Digital Repository, 2014.

  35. Yang Y, Shi J, Tolomelli G, Xu H, Xia J, Wang H et al. RARalpha2 expression confers myeloma stem cell features. Blood 2013; 122: 1437–1447.

    Article  CAS  Google Scholar 

  36. Hurt EM, Wiestner A, Rosenwald A, Shaffer AL, Campo E, Grogan T et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 2004; 5: 191–199.

    Article  CAS  Google Scholar 

  37. Romagnoli M, Trichet V, David C, Clement M, Moreau P, Bataille R et al. Significant impact of survivin on myeloma cell growth. Leukemia 2007; 21: 1070–1078.

    Article  CAS  Google Scholar 

  38. Yang Y, Shi J, Gu Z, Salama ME, Das S, Wendlandt E et al. Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res 2015; 75: 594–604.

    Article  CAS  Google Scholar 

  39. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    Article  CAS  Google Scholar 

  40. van Rhee F, Szymonifka J, Anaissie E, Nair B, Waheed S, Alsayed Y et al. Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood 2010; 116: 1220–1227.

    Article  CAS  Google Scholar 

  41. Seckinger A, Meissner T, Moreaux J, Depeweg D, Hillengass J, Hose K et al. Clinical and prognostic role of annexin A2 in multiple myeloma. Blood 2012; 120: 1087–1094.

    Article  CAS  Google Scholar 

  42. Hegde NS, Sanders DA, Rodriguez R, Balasubramanian S . The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem 2011; 3: 725–731.

    Article  CAS  Google Scholar 

  43. Sanders DA, Gormally MV, Marsico G, Beraldi D, Tannahill D, Balasubramanian S . FOXM1 binds directly to non-consensus sequences in the human genome. Genome Biol 2015; 16: 130.

    Article  Google Scholar 

  44. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011; 20: 620–634.

    Article  CAS  Google Scholar 

  45. Chang H, Jiang N, Jiang H, Saha MN, Qi C, Xu W et al. CKS1B nuclear expression is inversely correlated with p27Kip1 expression and is predictive of an adverse survival in patients with multiple myeloma. Haematologica 2010; 95: 1542–1547.

    Article  CAS  Google Scholar 

  46. Nischalke HD, Schmitz V, Luda C, Aldenhoff K, Berger C, Feldmann G et al. Detection of IGF2BP3, HOXB7, and NEK2 mRNA expression in brush cytology specimens as a new diagnostic tool in patients with biliary strictures. PLoS One 2012; 7: e42141.

    Article  CAS  Google Scholar 

  47. Calvisi DF, Pinna F, Ladu S, Pellegrino R, Simile MM, Frau M et al. Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC. Gut 2009; 58: 679–687.

    Article  CAS  Google Scholar 

  48. Zhou W, Yang Y, Xia J, Wang H, Salama ME, Xiong W et al. NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell 2013; 23: 48–62.

    Article  CAS  Google Scholar 

  49. Liu X, Gao Y, Lu Y, Zhang J, Li L, Yin F . Upregulation of NEK2 is associated with drug resistance in ovarian cancer. Oncol Rep 2014; 31: 745–754.

    Article  Google Scholar 

  50. Marina M, Saavedra HI . Nek2 and Plk4: prognostic markers, drivers of breast tumorigenesis and drug resistance. Front Biosci (Landmark Ed) 2014; 19: 352–365.

    Article  Google Scholar 

  51. Shi L, Wang S, Zangari M, Xu H, Cao TM, Xu C et al. Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget 2010; 1: 22–33.

    Google Scholar 

  52. Tanno T, Lim Y, Wang Q, Chesi M, Bergsagel PL, Matthews G et al. Growth Differentiating Factor 15 enhances the tumor initiating and self-renewal potential of multiple myeloma cells. Blood 2013; 123: 725–733.

    Article  Google Scholar 

  53. Ziv E, Dean E, Hu D, Martino A, Serie D, Curtin K et al. Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. Nat Commun 2015; 6: 7539.

    Article  CAS  Google Scholar 

  54. Hu Y, Zheng M, Gali R, Tian Z, Topal Gorgun G, Munshi NC et al. A novel rapid-onset high-penetrance plasmacytoma mouse model driven by deregulation of cMYC cooperating with KRAS12V in BALB/c mice. Blood Cancer J 2013; 3: e156.

    Article  CAS  Google Scholar 

  55. Dechow T, Steidle S, Gotze KS, Rudelius M, Behnke K, Pechloff K et al. GP130 activation induces myeloma and collaborates with MYC. J Clin Invest 2014; 124: 5263–5274.

    Article  Google Scholar 

  56. Tompkins VS, Rosean TR, Holman CJ, DeHoedt C, Olivier AK, Duncan KM et al. Adoptive B-cell transfer mouse model of human myeloma. Leukemia 2016; 30: 962–966.

    Article  CAS  Google Scholar 

  57. Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M et al. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 2012; 120: 376–385.

    Article  CAS  Google Scholar 

  58. Lee EC, Fitzgerald M, Bannerman B, Donelan J, Bano K, Terkelsen J et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res 2011; 17: 7313–7323.

    Article  CAS  Google Scholar 

  59. Duncan K, Rosean TR, Tompkins VS, Olivier A, Sompallae R, Zhan F et al. (18)F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib. Blood Cancer J 2013; 3: e165.

    Article  CAS  Google Scholar 

  60. Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA et al. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma 2015; 56: 3320–3328.

    Article  CAS  Google Scholar 

  61. Innocenti P, Woodward H, O'Fee L, Hoelder S . Expanding the scope of fused pyrimidines as kinase inhibitor scaffolds: synthesis and modification of pyrido[3,4-d]pyrimidines. Org Biomol Chem 2015; 13: 893–904.

    Article  CAS  Google Scholar 

  62. Hu CM, Zhu J, Guo XE, Chen W, Qiu XL, Ngo B et al. Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism. Oncogene 2015; 34: 1220–1230.

    Article  CAS  Google Scholar 

  63. Bhat UG, Halasi M, Gartel AL . FoxM1 is a general target for proteasome inhibitors. PLoS One 2009; 4: e6593.

    Article  Google Scholar 

  64. Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G et al. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 2015; 125: 90–101.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The expert technical assistance by Dr Xuefang Jing and the provision of NSG mice by Dr Weizhou Zhang (both Department of Pathology, University of Iowa) are gratefully acknowledged. Research funding in Germany (Heidelberg) was provided by the Dietmar Hopp Stiftung (Walldorf), the Systems Medicine program of the German Ministry of Education and Science (CLIOMMICS 01ZX1309), and the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich/Transregio TRR79). This work was supported in part by NIH Training Grant T32-HL07734 and National Natural Science Foundation of China (NNSFC) Grant 81250110552 (both to VT); by NCI R01CA152105, Leukemia & Lymphoma Society Translational Research Program Awards 6246-11 and 6094-12, NNSFC Award 81228016, Multiple Myeloma Research Foundation Senior Research Program Award 2015 and International Myeloma Foundation Senior Research Program Award 2015 (all to FZ); by institutional start-up funds from the Department of Internal Medicine, CCOM, UI (to FZ and GT); by NCI Core Grant P30CA086862 in support of The University of Iowa Holden Comprehensive Cancer Center; and by NCI R01CA151354 (to SJ).

Author information

Author notes

  1. C Gu and Y Yang: These author are co-first authors.

  2. F Zhan and S Janz: These author are co-senior authors.

Authors and Affiliations

  1. Basic Medical College, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China

    C Gu & Y Yang

  2. Department of Pathology, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA

    C Gu, R Sompallae, V S Tompkins, C Holman & S Janz

  3. Department of Internal Medicine, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA

    Y Yang, H Xu, G Tricot & F Zhan

  4. Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA

    R Sompallae

  5. Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany

    D Hose & H Goldschmidt

  6. Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany

    D Hose & H Goldschmidt

  7. Holden Comprehensive Cancer Center, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA

    G Tricot, F Zhan & S Janz

Authors
  1. C Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Sompallae
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V S Tompkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Holman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Hose
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Tricot
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Janz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to F Zhan or S Janz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, C., Yang, Y., Sompallae, R. et al. FOXM1 is a therapeutic target for high-risk multiple myeloma. Leukemia 30, 873–882 (2016). https://doi.org/10.1038/leu.2015.334

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.334

This article is cited by

Search

Advanced search

Quick links