ETV6/ RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia
| Autor: | Verónica Alonso-Pérez, Teresa González, Sandra Santos, Rocío Benito, Jesús María Hernández-Rivas, Jesus M Hernández-Sánchez, Ignacio García-Tuñón, Adrián Montaño, José Luis Ordóñez |
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| Přispěvatelé: | Junta de Castilla y León, Instituto de Salud Carlos III, Fundación Castellano Leonesa de Hematología y Hemoterapia, Fundación Memoria de D. Samuel Solorzano Barruso, Centro de Investigación Biomédica en Red Cáncer (España), Universidad de Salamanca, Asociación Española Contra el Cáncer |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
sistemas CRISPR-Cas acute lymphoblastic leukaemia leucemia linfoide Biology Acute lymphoblastic leukemia Article Fusion gene 03 medical and health sciences chemistry.chemical_compound ETV6/RUNX1 Fusion Gene CRISP/Cas9 0302 clinical medicine hemic and lymphatic diseases Genome edition Gene lcsh:QH301-705.5 ETV6/RUNX1 CRISPR/Cas9 PI3K/AKT/mTOR pathway genoma Genome Cell growth General Medicine Fusion protein Leukemia Lymphoid ETV6 030104 developmental biology RUNX1 chemistry lcsh:Biology (General) 030220 oncology & carcinogenesis Cancer research 3207.08 Hematología CRISPR-Cas Systems |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname GREDOS. Repositorio Institucional de la Universidad de Salamanca Fundacion Sancho el Sabio Fundazioa (FSS) Cells, Vol 9, Iss 1, p 215 (2020) Cells Volume 9 Issue 1 |
| Popis: | © 2020 by the authors. [Background]: The t(12;21)(p13;q22), which fuses ETV6 and RUNX1 genes, is the most common genetic abnormality in children with B-cell precursor acute lymphoblastic leukaemia. The implication of the fusion protein in leukemogenesis seems to be clear. However, its role in the maintenance of the disease continues to be controversial. [Methods]: Generation of an in vitro ETV6/RUNX1 knock out model using the CRISPR/Cas9 gene editing system. Functional characterization by RNA sequencing, proliferation assays, apoptosis and pharmacologic studies, and generation of edited-cell xenograft model. [Results]: The expression of ETV6/RUNX1 fusion gene was completely eliminated, thus generating a powerful model on which to study the role of the fusion gene in leukemic cells. The loss of fusion gene expression led to the deregulation of biological processes affecting survival such as apoptosis resistance and cell proliferation capacity. Tumour cells showed higher levels of apoptosis, lower proliferation rate and a greater sensitivity to PI3K inhibitors in vitro along as a decrease in tumour growth in xenografts models after ETV6/RUNX1 fusion gene abrogation. [Conclusions]: ETV6/RUNX1 fusion protein seems to play an important role in the maintenance of the leukemic phenotype and could thus become a potential therapeutic target. This work was financially supported in part by a grant from the Consejería de Educación, Junta de Castilla y León, Fondos FEDER (SA085U16, SA271P18), and the Regional Council of Castilla y León SACYL, (GRS 1847/A/18, GRS 2062/A/19), SYNtherapy. Synthetic Lethality for Personalized Therapy-based Stratification In Acute Leukaemia (ERAPERMED2018-275); ISCIII (AC18/00093), co-funded by ERDF/ESF, “Investing in your future”, Fundación Castellano Leonesa de Hematología y Hemoterapia (FUCALHH 2017), Proyectos de investigación en Biomedicina, gestión sanitaria y atención sociosanitaria del IBSAL (IBY17/00006), Fundación Memoria Don Samuel Solórzano Barruso, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233).JMHS is supported by a research grant by FEHH (“Fundación Española de Hematología y Hemoterapia”), and JLO is supported by a grant from the University of Salamanca (“Contrato postdoctoral programa II 2017-18”)., and AM by a grant from the Junta Provincial de Salamanca of the Asociación Española Contra el Cáncer (AECC). |
| Databáze: | OpenAIRE |
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