Etv6/Runx1 Fusion Gene Abrogation Decreases The Oncogenic Potencial Of Tumour Cells In A Preclinical Model Of Acute Lymphoblastic Leukaemia

Abstract

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 leukaemogenesis seems to be clear. However, its role in the maintenance of the disease continues to be controversial. Aim To eliminate the expression of the ETV6/RUNX1 fusion gene, in order to elucidate the effect in the leukaemic cells. Methods Generation of an in vitro ETV6/RUNX1 knock out model using the genetic modification system CRISPR/Cas9. Functional studies and generation of edited-cell xenograft model were carried out. Results For the first time, 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 leukaemic cells. ETV6/RUNX1 inactivation caused the deregulation of cellular processes that could be participating in the maintenance of the leukaemic phenotype, such as differentiation and lymphoid activation, apoptosis, cell signaling and cell migration. 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 plays a fundamental role in the maintenance of the leukaemic phenotype, thereby being making the fusion protein a potential therapeutic target.