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

© 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)