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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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.

Author information

Author notes

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

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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https://doi.org/10.1038/s41388-019-0746-1