Genome-Wide CRISPR-Cas9 screening identifies BRAF inhibitor as a sensitizer of dasatinib in treating T-acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia is an aggressive hematologic tumor with fewer treatment strategies. Dasatinib, an FDA-approved tyrosine kinase inhibitor applied in chronic myelogenous leukemia and acute lymphoblastic leukemia with Philadelphia chromosome-positive has been utilized in T-ALL for cure but the clinical outcomes are not satisfied, calling for further investigation on the mechanism and potential combinations to overcome resistance. In this study, we performed a genome-wide CRISPR-Cas9 screening and identified the MAPK pathway as an essential regulator of sensitivity to dasatinib. Then we confirmed that the inhibition of the MAPK pathway by dabrafenib could sensitize T-ALL cells to dasatinib in vitro and reveal the underlying mechanism by RNA sequencing. Together, we put forward a promising combining strategy for T-ALL. Comparative gene expression profiling analysis of RNA-seq data for Jurkat cells with different treatments (vehicle, dasatinib, and the combination of dasatinib and dabrafenib).