RT Journal Article
T1 Downregulation of Specific Fbxw7 Isoforms with Differential Effects in T-Cell Lymphoblastic Lymphoma
A1 Vázquez-Domínguez, Irene
A1 González-Sánchez, Laura
A1 López-Nieva, Pilar
A1 Fernández-Navarro, Pablo
A1 Villa-Morales, María
A1 Cobos-Fernández, María
A1 Sastre, Isabel
A1 Fraga, Mario
A1 Fernández, Agustín
A1 Malumbres, Marcos
A1 Salazar Roa, María
A1 Graña-Castro, Osvaldo
A1 Santos, Javier
A1 Llamas, Pilar
A1 López-Lorenzo, José
A1 Fernández-Piqueras, José
AB 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.
PB Springer
SN 0950-9232
YR 2019
FD 2019
LK https://hdl.handle.net/20.500.14352/98008
UL https://hdl.handle.net/20.500.14352/98008
LA eng
NO 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
NO FundingSpanish 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.
NO Fundación Ramón Areces
NO Banco de Santander
NO Asociación Española Contra el Cáncer
NO Comunidad de Madrid
NO Ministerio de Economía y Competitividad (España)
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 16 abr 2025