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Targeting Metabolic Reprogramming in Acute Myeloid Leukemia
Open AccessArticle

ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia

1
IBSAL, IBMCC, Cancer Research Center, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
2
Department of Biochemistry and Molecular Biology, University of Salamanca, Campus Unamuno s/n, 37007 Salamanca, Spain
3
Department of Hematology, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
4
Department of Medicine, Universidad de Salamanca and CIBERONC, 37007 Salamanca, Spain
*
Authors to whom correspondence should be addressed.
These authors share senior authorship.
Cells 2020, 9(1), 215; https://doi.org/10.3390/cells9010215 (registering DOI)
Received: 7 December 2019 / Revised: 9 January 2020 / Accepted: 13 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)
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. View Full-Text
Keywords: acute lymphoblastic leukaemia; ETV6/RUNX1; CRISPR/Cas9; genome edition acute lymphoblastic leukaemia; ETV6/RUNX1; CRISPR/Cas9; genome edition
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Montaño, A.; Ordoñez, J.L.; Alonso-Pérez, V.; Hernández-Sánchez, J.; Santos, S.; González, T.; Benito, R.; García-Tuñón, I.; Hernández-Rivas, J.M. ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia. Cells 2020, 9, 215.

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