In this study, we elucidated the molecular mechanisms of ZNF384-mediated FLT3 activation in ZNF384-r ALL and identified cis-regulatory elements responsible for transcriptional activation of FLT3. We further evaluated therapeutic potential of gilteritinib23,24, an FLT3 inhibitor, in ZNF384-r ALL in vitro and in vivo, pointing to potential genomics-guided targeted therapy for this patient population. Here, FLT3 is linked to acute lymphoblastic leukemia.