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.

FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma

Oncogene volume 40, pages 2182–2199 (2021)Cite this article

Subjects

Abstract

The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein, we demonstrate that Forkhead Box F1 (FOXF1) transcription factor is uniquely expressed in FP-RMS and is required for FP-RMS tumorigenesis. The PAX3-FOXO1 directly binds to FOXF1 enhancers and induces FOXF1 gene expression. CRISPR/Cas9 mediated inactivation of either FOXF1 coding sequence or FOXF1 enhancers suppresses FP-RMS tumorigenesis even in the presence of PAX3-FOXO1 oncogene. Knockdown or genetic knockout of FOXF1 induces myogenic differentiation in PAX3-FOXO1-positive FP-RMS. Over-expression of FOXF1 decreases myogenic differentiation in primary human myoblasts. In FP-RMS tumor cells, FOXF1 protein binds chromatin near enhancers associated with FP-RMS gene signature. FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors MYOD1 and MYOG to regulate FP-RMS-specific gene expression. Altogether, FOXF1 functions downstream of PAX3-FOXO1 to promote FP-RMS tumorigenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Fig. 1: FOXF1 expressed in fusion-positive FP-RMS tumors.
Fig. 2: FOXF1 is a direct transcriptional target of the PAX3-FOXO1 protein.
Fig. 3: FOXF1 is required for PAX3-FOXO1 to drive FP-RMS tumor growth.
Fig. 4: FOXF1 regulates expression of genes critical for FP-RMS tumor growth and metastasis.
Fig. 5: Ectopic expression of FOXF1 in primary human skeletal muscle myoblasts inhibits myogenic differentiation.
Fig. 6: FOXF1 DNA-binding is associated with active enhancers and with binding of PAX3-FOXO1 and myogenic transcription factors.
Fig. 7: FOXF1 binds to enhancers of genes associated with FP-RMS gene signature.
Fig. 8: FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors to activate the ERRFI1 enhancer.

References

  1. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer. 2009;115:4218–26.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Taylor AC, Shu L, Danks MK, Poquette CA, Shetty S, Thayer MJ, et al. P53 mutation and MDM2 amplification frequency in pediatric rhabdomyosarcoma tumors and cell lines. Med Pediatr Oncol. 2000;35:96–103.

    Article  CAS  PubMed  Google Scholar 

  3. Stratton MR, Fisher C, Gusterson BA, Cooper CS. Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction. Cancer Res. 1989;49:6324–7.

    CAS  PubMed  Google Scholar 

  4. Chen L, Shern JF, Wei JS, Yohe ME, Song YK, Hurd L, et al. Clonality and evolutionary history of rhabdomyosarcoma. PLoS Genet. 2015;11:e1005075.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chen X, Stewart E, Shelat AA, Qu C, Bahrami A, Hatley M, et al. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell. 2013;24:710–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Taylor JGT, Cheuk AT, Tsang PS, et al. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest. 2009;119:3395–407.

    CAS  PubMed  Google Scholar 

  7. Stewart E, McEvoy J, Wang H, Chen X, Honnell V, Ocarz M, et al. Identification of therapeutic targets in rhabdomyosarcoma through integrated genomic, epigenomic, and proteomic analyses. Cancer Cell. 2018;34:411–26.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014;4:216–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol. 2002;20:2672–9.

    Article  CAS  Google Scholar 

  10. Rudzinski ER, Anderson JR, Chi YY, Gastier-Foster JM, Astbury C, Barr FG, et al. Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer. 2017;64: https://doi.org/10.1002/pbc.26645.

  11. Cao L, Yu Y, Bilke S, Walker RL, Mayeenuddin LH, Azorsa DO, et al. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res. 2010;70:6497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gryder BE, Yohe ME, Chou HC, Zhang X, Marques J, Wachtel M, et al. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Disco. 2017;7:884–99.

    Article  CAS  Google Scholar 

  13. Otabe O, Kikuchi K, Tsuchiya K, Katsumi Y, Yagyu S, Miyachi M, et al. MET/ERK2 pathway regulates the motility of human alveolar rhabdomyosarcoma cells. Oncol Rep. 2017;37:98–104.

    Article  PubMed  Google Scholar 

  14. Taulli R, Scuoppo C, Bersani F, Accornero P, Forni PE, Miretti S, et al. Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Res. 2006;66:4742–9.

    Article  CAS  PubMed  Google Scholar 

  15. Schoffski P, Adkins D, Blay JY, Gil T, Elias AD, Rutkowski P, et al. An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours. Eur J Cancer. 2013;49:3219–28.

    Article  CAS  PubMed  Google Scholar 

  16. Pappo AS, Vassal G, Crowley JJ, Bolejack V, Hogendoorn PC, Chugh R, et al. A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study. Cancer. 2014;120:2448–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schoffski P, Wozniak A, Leahy MG, Aamdal S, Rutkowski P, Bauer S, et al. The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’. Eur J Cancer. 2018;94:156–67.

    Article  CAS  PubMed  Google Scholar 

  18. Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 2006;66:6936–46.

    Article  CAS  Google Scholar 

  19. Williamson D, Missiaglia E, de Reynies A, Pierron G, Thuille B, Palenzuela G, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 2010;28:2151–8.

    Article  Google Scholar 

  20. Lae M, Ahn EH, Mercado GE, Chuai S, Edgar M, Pawel BR, et al. Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas. J Pathol. 2007;212:143–51.

    Article  CAS  PubMed  Google Scholar 

  21. Wachtel M, Dettling M, Koscielniak E, Stegmaier S, Treuner J, Simon-Klingenstein K, et al. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res. 2004;64:5539–45.

    Article  CAS  PubMed  Google Scholar 

  22. Mercado GE, Xia SJ, Zhang C, Ahn EH, Gustafson DM, Lae M, et al. Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: focus on MYCN as a biologically relevant target. Genes Chromosomes Cancer. 2008;47:510–20.

    Article  CAS  PubMed  Google Scholar 

  23. Mahlapuu M, Ormestad M, Enerback S, Carlsson P. The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm. Development. 2001;128:155–66.

    Article  CAS  PubMed  Google Scholar 

  24. Kalinichenko VV, Zhou Y, Bhattacharyya D, Kim W, Shin B, Bambal K, et al. Haploinsufficiency of the mouse Forkhead Box f1 gene causes defects in gall bladder development. J Biol Chem. 2002;277:12369–74.

    Article  CAS  PubMed  Google Scholar 

  25. Ustiyan V, Bolte C, Zhang Y, Han L, Xu Y, Yutzey KE, et al. FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme. Dev Biol. 2018;443:50–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ren X, Ustiyan V, Guo M, Wang G, Bolte C, Zhang Y, et al. Postnatal alveologenesis depends on FOXF1 signaling in c-KIT(+) endothelial progenitor cells. Am J Respir Crit Care Med. 2019;200:1164–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hoggatt AM, Kim JR, Ustiyan V, Ren X, Kalin TV, Kalinichenko VV, et al. The transcription factor Foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells. J Biol Chem. 2013;288:28477–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hinson AR, Jones R, Crose LE, Belyea BC, Barr FG, Linardic CM. Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls. Front Oncol. 2013;3:183.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gryder BE, Wachtel M, Chang K, El Demerdash O, Aboreden NG, Mohammed W, et al. Miswired enhancer logic drives a cancer of the muscle lineage. iScience. 2020;23:101103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ren X, Zhang Y, Snyder J, Cross ER, Shah TA, Kalin TV, et al. Forkhead box M1 transcription factor is required for macrophage recruitment during liver repair. Mol Cell Biol. 2010;30:5381–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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;288:22527–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ustiyan V, Wert SE, Ikegami M, Wang IC, Kalin TV, Whitsett JA, et al. Foxm1 transcription factor is critical for proliferation and differentiation of Clara cells during development of conducting airways. Dev Biol. 2012;370:198–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Black M, Milewski D, Le T, Ren X, Xu Y, Kalinichenko VV, et al. FOXF1 inhibits pulmonary fibrosis by preventing CDH2-CDH11 cadherin switch in myofibroblasts. Cell Rep. 2018;23:442–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Black M, Arumugam P, Shukla S, Pradhan A, Ustiyan V, Milewski D, et al. FOXM1 nuclear transcription factor translocates into mitochondria and inhibits oxidative phosphorylation. Mol Biol Cell. 2020;31:1411–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goda C, Balli D, Black M, Milewski D, Le T, Ustiyan V, et al. Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway. PLoS Genet. 2020;16:e1008692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sun L, Ren X, Wang IC, Pradhan A, Zhang Y, Flood HM, et al. The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice. Sci Signal. 2017;10:eaai8583

    Article  PubMed  Google Scholar 

  37. Bolte C, Flood HM, Ren X, Jagannathan S, Barski A, Kalin TV, et al. FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy. Sci Rep. 2017;7:10690.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Vallabh S, Kartashov AV, Barski A. Analysis of ChIP-Seq and RNA-Seq data with BioWardrobe. Methods Mol Biol. 2018;1783:343–60.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kartashov AV, Barski A. BioWardrobe: an integrated platform for analysis of epigenomics and transcriptomics data. Genome Biol. 2015;16:158.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Machanick P, Bailey TL. MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics. 2011;27:1696–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shao Z, Zhang Y, Yuan GC, Orkin SH, Waxman DJ. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets. Genome Biol. 2012;13:R16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gryder BE, Wu L, Woldemichael GM, Pomella S, Quinn TR, Park PMC, et al. Chemical genomics reveals histone deacetylases are required for core regulatory transcription. Nat Commun. 2019;10:3004.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tenente IM, Hayes MN, Ignatius MS, McCarthy K, Yohe M, Sindiri S, et al. Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma. Elife. 2017;6:e19214.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gryder BE, Khan J, Stanton BZ. Measurement of differential chromatin interactions with absolute quantification of architecture (AQuA-HiChIP). Nat Protoc. 2020;15:1209–36.

    Article  CAS  PubMed  Google Scholar 

  45. Robinson JT, Turner D, Durand NC, Thorvaldsdottir H, Mesirov JP, Aiden EL. Juicebox.js provides a cloud-based visualization system for Hi-C data. Cell Syst. 2018;6:256–8 e1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Milewski D, Balli D, Ustiyan V, Le T, Dienemann H, Warth A, et al. FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas. PLoS Genet. 2017;13:e1007097.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bolte C, Ren X, Tomley T, Ustiyan V, Pradhan A, Hoggatt A, et al. Forkhead box F2 regulation of platelet-derived growth factor and myocardin/serum response factor signaling is essential for intestinal development. J Biol Chem. 2015;290:7563–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cheng X-H, Black M, Ustiyan V, Le T, Fulford L, Sridharan A, et al. SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. PLoS Genet. 2014;10:e1004656.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kalin TV, Meliton L, Meliton AY, Zhu X, Whitsett JA, Kalinichenko VV. Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene. Am J Respir Cell Mol Biol. 2008;39:390–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gryder BE, Pomella S, Sayers C, Wu XS, Song Y, Chiarella AM, et al. Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma. Nat Genet. 2019;51:1714–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Szafranski P, Dharmadhikari AV, Wambach JA, Towe CT, White FV, Grady RM, et al. Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A. 2014;164A:2013–9.

    Article  PubMed  Google Scholar 

  52. Thakore PI, D’Ippolito AM, Song L, Safi A, Shivakumar NK, Kabadi AM, et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods. 2015;12:1143–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol. 2016;40:224–35.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mehner C, Miller E, Khauv D, Nassar A, Oberg AL, Bamlet WR, et al. Tumor cell-derived MMP3 orchestrates Rac1b and tissue alterations that promote pancreatic adenocarcinoma. Mol Cancer Res. 2014;12:1430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ebauer M, Wachtel M, Niggli FK, Schafer BW. Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR. Oncogene. 2007;26:7267–81.

    Article  CAS  PubMed  Google Scholar 

  56. Hakozaki M, Hojo H, Tajino T, Yamada H, Kikuchi S, Kikuta A, et al. Therapeutic cytodifferentiation in alveolar rhabdomyosarcoma without genetic change of the PAX3-FKHR chimeric fusion gene: a case study. Hum Cell. 2013;26:149–54.

    Article  PubMed  Google Scholar 

  57. Smith LM, Anderson JR, Coffin CM. Cytodifferentiation and clinical outcome after chemotherapy and radiation therapy for rhabdomyosarcoma (RMS). Med Pediatr Oncol. 2002;38:398–404.

    Article  PubMed  Google Scholar 

  58. Jothi M, Nishijo K, Keller C, Mal AK. AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell. Cell Cycle. 2012;11:895–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Skrzypek K, Kusienicka A, Trzyna E, Szewczyk B, Ulman A, Konieczny P, et al. SNAIL is a key regulator of alveolar rhabdomyosarcoma tumor growth and differentiation through repression of MYF5 and MYOD function. Cell Death Dis. 2018;9:643.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Feng Y, Ngu H, Alford SK, Ward M, Yin F, Longmore GD. alpha-actinin1 and 4 tyrosine phosphorylation is critical for stress fiber establishment, maintenance and focal adhesion maturation. Exp Cell Res. 2013;319:1124–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Davicioni E, Anderson MJ, Finckenstein FG, Lynch JC, Qualman SJ, Shimada H, et al. Molecular classification of rhabdomyosarcoma–genotypic and phenotypic determinants of diagnosis: a report from the Children’s Oncology Group. Am J Pathol. 2009;174:550–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Williamson D, Lu YJ, Gordon T, Sciot R, Kelsey A, Fisher C, et al. Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype. J Clin Oncol. 2005;23:880–8.

    Article  CAS  PubMed  Google Scholar 

  63. Cairns J, Fridley BL, Jenkins GD, Zhuang Y, Yu J, Wang L. Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation. EMBO Rep. 2018;19:e44767.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Cai Y, Bolte C, Le T, Goda C, Xu Y, Kalin TV, et al. FOXF1 maintains endothelial barrier function and prevents edema after lung injury. Sci Signal. 2016;9:ra40.

    Article  PubMed  Google Scholar 

  65. Ren X, Ustiyan V, Pradhan A, Cai Y, Havrilak JA, Bolte CS, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014;115:709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pradhan A, Dunn A, Ustiyan V, Bolte C, Wang G, Whitsett JA, et al. The S52F FOXF1 mutation inhibits STAT3 signaling and causes alveolar capillary dysplasia. Am J Respir Crit Care Med. 2019;200:1045–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang S, Yan S, Zhu S, Zhao Y, Yan J, Xiao Z, et al. FOXF1 induces epithelial-mesenchymal transition in colorectal cancer metastasis by transcriptionally activating SNAI1. Neoplasia. 2018;20:996–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nilsson G, Kannius-Janson M. Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling. BMC Cancer. 2016;16:142.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lo PK, Lee JS, Liang X, Han L, Mori T, Fackler MJ, et al. Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer. Cancer Res. 2010;70:6047–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Milewski D, Pradhan A, Wang X, Cai Y, Le T, Turpin B, et al. FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21(Cip1) CDK inhibitor. Oncogene. 2017;36:850–62.

    Article  CAS  PubMed  Google Scholar 

  71. d’Amore ES, Tollot M, Stracca-Pansa V, Menegon A, Meli S, Carli M, et al. Therapy associated differentiation in rhabdomyosarcomas. Mod Pathol. 1994;7:69–75.

    PubMed  Google Scholar 

  72. Kikuchi K, Tsuchiya K, Otabe O, Gotoh T, Tamura S, Katsumi Y, et al. Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma. Biochem Biophys Res Commun. 2008;365:568–74.

    Article  CAS  PubMed  Google Scholar 

  73. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120:1570–80. quiz 752

    Article  CAS  PubMed  Google Scholar 

  74. Zhang Y, Guan DX, Shi J, Gao H, Li JJ, Zhao JS, et al. All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer. J Hepatol. 2013;59:1255–63.

    Article  CAS  PubMed  Google Scholar 

  75. Brewster AM, Lee JJ, Clayman GL, Clifford JL, Reyes MJ, Zhou X, et al. Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol. 2007;25:1974–8.

    Article  CAS  PubMed  Google Scholar 

  76. Rekhi B, Gupta C, Chinnaswamy G, Qureshi S, Vora T, Khanna N, et al. Clinicopathologic features of 300 rhabdomyosarcomas with emphasis upon differential expression of skeletal muscle specific markers in the various subtypes: a single institutional experience. Ann Diagn Pathol. 2018;36:50–60.

    Article  PubMed  Google Scholar 

  77. Liu QC, Zha XH, Faralli H, Yin H, Louis-Jeune C, Perdiguero E, et al. Comparative expression profiling identifies differential roles for Myogenin and p38alpha MAPK signaling in myogenesis. J Mol Cell Biol. 2012;4:386–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dias P, Chen B, Dilday B, Palmer H, Hosoi H, Singh S, et al. Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass. Am J Pathol. 2000;156:399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhao Z, Yin Y, Zhang J, Qi J, Zhang D, Ma Y, et al. Spindle cell/sclerosing rhabdomyosarcoma: case series from a single institution emphasizing morphology, immunohistochemistry and follow-up. Int J Clin Exp Pathol. 2015;8:13814–20.

    PubMed  PubMed Central  Google Scholar 

  80. Sun W, Chatterjee B, Wang Y, Stevenson HS, Edelman DC, Meltzer PS, et al. Distinct methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcoma. Mod Pathol. 2015;28:1214–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Tien Le for technical assistance. This work was supported by the NIH grants R01 CA142724 (TVK), R01 HL132849 (TVK), R01 HL141174 (VVK).

Author information

Author notes

  1. David Milewski

    Present address: Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

Authors and Affiliations

  1. Division of Pulmonary Biology, The Perinatal Institute of Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    David Milewski, Samriddhi Shukla, Arun Pradhan, Johnny Donovan, Parvathi Sudha, Athena Pyros, Yan Xu, Vladimir V. Kalinichenko & Tanya V. Kalin

  2. Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Berkley E. Gryder & Javed Khan

  3. Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Sushmitha Vallabh & Artem Barski

  4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Yan Xu, Artem Barski, Sara Szabo, Brian Turpin, Joseph G. Pressey, Douglas P. Millay, Vladimir V. Kalinichenko & Tanya V. Kalin

  5. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Artem Barski

  6. Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Sara Szabo

  7. Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Brian Turpin & Joseph G. Pressey

  8. Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Douglas P. Millay

  9. Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Vladimir V. Kalinichenko

Authors
  1. David Milewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samriddhi Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Berkley E. Gryder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arun Pradhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johnny Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Parvathi Sudha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sushmitha Vallabh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Athena Pyros
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Artem Barski
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sara Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Brian Turpin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Joseph G. Pressey
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Douglas P. Millay
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Javed Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Vladimir V. Kalinichenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tanya V. Kalin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tanya V. Kalin.

Ethics declarations

Conflict of interest

The work of TVK is supported by NIH (R01CA142724, R01HL132849), the work of VVK is supported by NIH (R01HL141174). AB is a co-founder of Datirium, LLC, the developer of SciDAP data analysis platform. Other authors declare no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Milewski, D., Shukla, S., Gryder, B.E. et al. FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma. Oncogene 40, 2182–2199 (2021). https://doi.org/10.1038/s41388-021-01694-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01694-9

This article is cited by

Search

Advanced search

Quick links