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Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma

Oncogene volume 38, pages 4620–4636 (2019)Cite this article

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Abstract

FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7β isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7 expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the β-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua non condition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7 isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.

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References

  1. Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83–93.

    Article  CAS  Google Scholar 

  2. Knuutila S, Aalto Y, Autio K, Björkqvist AM, El-Rifai W, Hemmer S, et al. DNA copy number losses in human neoplasms. Am J Pathol. 1999;155:683–94.

    Article  CAS  Google Scholar 

  3. Spruck CH, Strohmaier H, Sangfelt O, Müller HM, Hubalek M, Müller-Holzner E, et al. hCDC4 gene mutations in endometrial cancer. Cancer Res. 2002;62:4535–9.

    CAS  PubMed  Google Scholar 

  4. Ho MS, Tsai P-I, Chien C-T. F-box proteins: the key to protein degradation. J Biomed Sci. 2006;13:181–91.

    Article  CAS  Google Scholar 

  5. Crusio KM, King B, Reavie LB, Aifantis I. The ubiquitous nature of cancer: the role of the SCF(Fbw7) complex in development and transformation. Oncogene. 2010;29:4865–73.

    Article  CAS  Google Scholar 

  6. Xu W, Taranets L, Popov N. Regulating Fbw7 on the road to cancer. Semin Cancer Biol. 2016;36:62–70.

    Article  CAS  Google Scholar 

  7. Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, et al. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 2007;67:9006–12.

    Article  CAS  Google Scholar 

  8. Davis RJ, Welcker M, Clurman BE. Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell. 2014;26:455–64.

    Article  CAS  Google Scholar 

  9. Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M, et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica. 2009;94:1383–90.

    Article  CAS  Google Scholar 

  10. Bonn BR, Rohde M, Zimmermann M, Krieger D, Oschlies I, Niggli F, et al. Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood. 2013;121:3153–60.

    Article  CAS  Google Scholar 

  11. Callens C, Baleydier F, Lengline E, Ben Abdelali R, Petit A, Villarese P, et al. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma. J Clin Oncol. 2012;30:1966–73.

    Article  CAS  Google Scholar 

  12. Larson Gedman A, Chen Q, Kugel Desmoulin S, Ge Y, LaFiura K, Haska CL, et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia. 2009;23:1417–25.

    Article  CAS  Google Scholar 

  13. Neumann M, Vosberg S, Schlee C, Heesch S, Schwartz S, Gökbuget N, et al. Mutational spectrum of adult T-ALL. Oncotarget. 2015;6:2754–66.

    Article  Google Scholar 

  14. Park M-J, Taki T, Oda M, Watanabe T, Yumura-Yagi K, Kobayashi R, et al. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol. 2009;145:198–206.

    Article  CAS  Google Scholar 

  15. Balamurugan K, Wang J-M, Tsai H-H, Sharan S, Anver M, Leighty R, et al. The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO J. 2010;29:4106–17.

    Article  CAS  Google Scholar 

  16. Feng D-D, Zhang H, Zhang P, Zheng Y-S, Zhang X-J, Han B-W, et al. Down-regulated miR-331-5p and miR-27a are associated with chemotherapy resistance and relapse in leukaemia. J Cell Mol Med. 2011;15:2164–75.

    Article  CAS  Google Scholar 

  17. Kimura T, Gotoh M, Nakamura Y, Arakawa H. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53. Cancer Sci. 2003;94:431–6.

    Article  CAS  Google Scholar 

  18. Mao J-H, Perez-Losada J, Wu D, Delrosario R, Tsunematsu R, Nakayama KI, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature. 2004;432:775–9.

    Article  CAS  Google Scholar 

  19. Wang L, Ye X, Liu Y, Wei W, Wang Z. Aberrant regulation of FBW7 in cancer. Oncotarget. 2014;5:2000–15.

    PubMed  PubMed Central  Google Scholar 

  20. Akhoondi S, Lindström L, Widschwendter M, Corcoran M, Bergh J, Spruck C, et al. Inactivation of FBXW7/hCDC4-β expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer. Breast Cancer Res. 2010;12:R105.

    Article  CAS  Google Scholar 

  21. Cheng Y, Chen G, Martinka M, Ho V, Li G. Prognostic significance of Fbw7 in human melanoma and its role in cell migration. J Invest Dermatol. 2013;133:1794–802.

    Article  CAS  Google Scholar 

  22. Gu Z, Inomata K, Mitsui H, Horii A. Promoter hypermethylation is not the major mechanism for inactivation of the FBXW7 beta-form in human gliomas. Genes Genet Syst. 2008;83:347–52.

    Article  CAS  Google Scholar 

  23. Sionov RV, Netzer E, Shaulian E. Differential regulation of FBXW7 isoforms by various stress stimuli. Cell Cycle. 2013;12:3547–54.

    Article  CAS  Google Scholar 

  24. de Leval L, Bisig B, Thielen C, Boniver J, Gaulard P. Molecular classification of T-cell lymphomas. Crit Rev Oncol Hematol. 2009;72:125–43.

    Article  Google Scholar 

  25. Aifantis I, Raetz E, Buonamici S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol. 2008;8:380–90.

    Article  CAS  Google Scholar 

  26. Van Vlierberghe P, Ferrando A. The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest. 2012;122:3398–406.

    Article  Google Scholar 

  27. Burkhardt B. Paediatric lymphoblastic T-cell leukaemia and lymphoma: one or two diseases? Br J Haematol. 2010;149:653–68.

    Article  CAS  Google Scholar 

  28. Khoury MP, Bourdon J-C. The isoforms of the p53 protein. Cold Spring Harb Perspect Biol. 2010;2:a000927.

    Article  Google Scholar 

  29. Grinkevich VV, Nikulenkov F, Shi Y, Enge M, Bao W, Maljukova A, et al. Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. Cancer Cell. 2009;15:441–53.

    Article  CAS  Google Scholar 

  30. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622–9.

    Article  CAS  Google Scholar 

  31. Correia NC, Durinck K, Leite AP, Ongenaert M, Rondou P, Speleman F, et al. Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia. Leukemia. 2013;27:1603–6.

    Article  CAS  Google Scholar 

  32. Huang H, Ma L, Li J, Yu Y, Zhang D, Wei J, et al. NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression. Oncotarget. 2014;5:493–505.

    PubMed  PubMed Central  Google Scholar 

  33. Kumar V, Palermo R, Talora C, Campese AF, Checquolo S, Bellavia D, et al. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia. 2014;28:2324–35.

    Article  CAS  Google Scholar 

  34. Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med. 2013;210:1545–57.

    Article  CAS  Google Scholar 

  35. Zhou Z, He C, Wang J. Regulation mechanism of Fbxw7-related signaling pathways (Review). Oncol Rep. 2015;34:2215–24.

    Article  CAS  Google Scholar 

  36. Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Akhondi S, Corcoran M, et al. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res. 2007;67:5611–6.

    Article  CAS  Google Scholar 

  37. Kalender Atak Z, De Keersmaecker K, Gianfelici V, Geerdens E, Vandepoel R, Pauwels D, et al. High accuracy mutation detection in leukemia on a selected panel of cancer genes. PLoS ONE. 2012;7:e38463.

    Article  Google Scholar 

  38. Sancho R, Blake SM, Tendeng C, Clurman BE, Lewis J, Behrens A. Fbw7 repression by hes5 creates a feedback loop that modulates Notch-mediated intestinal and neural stem cell fate decisions. PLoS Biol. 2013;11:e1001586.

    Article  CAS  Google Scholar 

  39. Kourtis N, Moubarak RS, Aranda-Orgilles B, Lui K, Aydin IT, Trimarchi T, et al. FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification. Nat Cell Biol. 2015;17:322–32.

    Article  Google Scholar 

  40. Yumimoto K, Akiyoshi S, Ueo H, Sagara Y, Onoyama I, Ueo H, et al. F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. J Clin Invest. 2015;125:621–35.

    Article  Google Scholar 

  41. Rocher-Ros V, Marco S, Mao J-H, Gines S, Metzger D, Chambon P, et al. Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7. Oncogene. 2010;29:2950–61.

    Article  CAS  Google Scholar 

  42. Trausch-Azar JS, Abed M, Orian A, Schwartz AL. Isoform-specific SCF(Fbw7) ubiquitination mediates differential regulation of PGC-1α. J Cell Physiol. 2015;230:842–52.

    Article  CAS  Google Scholar 

  43. Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell. 2001;8:971–82.

    Article  CAS  Google Scholar 

  44. Wei X, Tang C, Lu X, Liu R, Zhou M, He D, et al. MiR-101 targets DUSP1 to regulate the TGF-β secretion in sorafenib inhibits macrophage-induced growth of hepatocarcinoma. Oncotarget. 2015;6:18389–405.

    PubMed  PubMed Central  Google Scholar 

  45. O’Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007;204:1813–24.

    Article  Google Scholar 

  46. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med. 2007;204:1825–35.

    Article  CAS  Google Scholar 

  47. Tremblay CS, Curtis DJ. The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia. Curr Opin Hematol. 2014;21:320–5.

    Article  CAS  Google Scholar 

  48. King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, et al. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell. 2013;153:1552–66.

    Article  CAS  Google Scholar 

  49. Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, et al. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes Dev. 2008;22:986–91.

    Article  CAS  Google Scholar 

  50. Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alborán IM, Nakayama K, et al. Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med. 2007;204:2875–88.

    Article  CAS  Google Scholar 

  51. Gu Z, Mitsui H, Inomata K, Honda M, Endo C, Sakurada A, et al. The methylation status of FBXW7 beta-form correlates with histological subtype in human thymoma. Biochem Biophys Res Commun. 2008;377:685–8.

    Article  CAS  Google Scholar 

  52. Lai EC. Two decades of miRNA biology: lessons and challenges. RNA. 2015;21:675–7.

    Article  CAS  Google Scholar 

  53. Katt ME, Placone AL, Wong AD, Xu ZS, Searson PC. In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front Bioeng Biotechnol 2016;4; https://doi.org/10.3389/fbioe.2016.00012.

  54. Mavrakis KJ, Van Der Meulen J, Wolfe AL, Liu X, Mets E, Taghon T, et al. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet. 2011;43:673–8.

    Article  CAS  Google Scholar 

  55. Mussolin L, Holmes AB, Romualdi C, Sales G, D’Amore ESG, Ghisi M, et al. An aberrant microRNA signature in childhood T-cell lymphoblastic lymphoma affecting CDKN1B expression, NOTCH1 and growth factor signaling pathways. Leukemia. 2014;28:1909–12.

    Article  CAS  Google Scholar 

  56. Hu J, Wu C, Zhao X, Liu C. The prognostic value of decreased miR-101 in various cancers: a meta-analysis of 12 studies. Onco Targets Ther. 2017;10:3709–18.

    Article  Google Scholar 

  57. Welcker M, Orian A, Jin J, Grim JE, Grim JA, Harper JW, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA. 2004;101:9085–90.

    Article  CAS  Google Scholar 

  58. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.

    Article  CAS  Google Scholar 

  59. Andrés-León E, González Peña D, Gómez-López G, Pisano DG. miRGate: a curated database of human, mouse and rat miRNA-mRNA targets. Database (Oxf). 2015;2015:bav035.

    Google Scholar 

  60. Mullokandov G, Baccarini A, Ruzo A, Jayaprakash AD, Tung N, Israelow B, et al. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nat Methods. 2012;9:840–6.

    Article  CAS  Google Scholar 

  61. van Drogen F, Sangfelt O, Malyukova A, Matskova L, Yeh E, Means AR, et al. Ubiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms. Mol Cell. 2006;23:37–48.

    Article  Google Scholar 

  62. Guo D, Ye J, Dai J, Li L, Chen F, Ma D, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res. 2009;33:678–85.

    Article  CAS  Google Scholar 

  63. Jin HY, Gonzalez-Martin A, Miletic AV, Lai M, Knight S, Sabouri-Ghomi M, et al. Transfection of microRNA Mimics Should Be Used with Caution. Front Genet. 2015;6:340.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Spanish Biobanks for providing us with the T-LBL samples to elaborate this work. Dr. Grim (Fred Hutchinson Cancer Research Centre) and Dr. Van Santen (CBMSO) for providing us with the CMV-FBXW7 constructs and packing vectors for retroviral transduction, respectively. The Cytometry, Cell Culture and Genomic services of the CBMSO for technical support. We thank Dr. Iria González-Vasconcellos (CBMSO-UAM) for the critical reading of this paper.

Funding

Spanish Ministry of Economy and Competitiveness (SAF2015-70561-R; MINECO/FEDER, EU; BES-2013-065740); the Autonomous Community of Madrid, Spain (B2017/BMD-3778; LINFOMAS-CM); the Spanish Association against Cancer (AECC, 2018; PROYE18054PIRI) and the Instituto de Salud Carlos III (ISCIII) (ACCI-CIBERER-17). Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledged.

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  1. These authors contributed equally: Irene Vázquez-Domínguez, Laura González-Sánchez

Authors and Affiliations

  1. Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain

    Irene Vázquez-Domínguez, Laura González-Sánchez, Pilar López-Nieva, María Villa-Morales, María Á. Cobos-Fernández, Isabel Sastre, Javier Santos & José Fernández-Piqueras

  2. IIS Fundación Jiménez Díaz, Madrid, Spain

    Irene Vázquez-Domínguez, Laura González-Sánchez, Pilar López-Nieva, María Villa-Morales, María Á. Cobos-Fernández, Javier Santos, Pilar Llamas, José L. López-Lorenzo & José Fernández-Piqueras

  3. Consorcio de Investigación Biomédica de Enfermedades Raras (CIBERER), Madrid, Spain

    Laura González-Sánchez, Pilar López-Nieva, María Villa-Morales, Javier Santos & José Fernández-Piqueras

  4. Unidad de Epidemiología Ambiental y Cáncer, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain

    Pablo Fernández-Navarro

  5. Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

    Pablo Fernández-Navarro

  6. Centro de Investigación en Nanomateriales y Nanotecnología (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Oviedo, Spain

    Mario F. Fraga

  7. Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Fundación para la Investigación Biosanitaria de Asturias (FINBA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA-HUCA), Oviedo, Spain

    Agustín F. Fernández

  8. Grupo de División Celular y Cáncer, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    Marcos Malumbres & María Salazar-Roa

  9. Unidad de Bioinformática, Biología Estructural y Biocomputación, Centro Nacional de Investigaciones Ocológicas (CNIO), Madrid, Spain

    Osvaldo Graña-Castro

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  1. Irene Vázquez-Domínguez
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Vázquez-Domínguez, I., González-Sánchez, L., López-Nieva, P. et al. Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma. Oncogene 38, 4620–4636 (2019). https://doi.org/10.1038/s41388-019-0746-1

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