In line with the activation of genes positively regulated by LSD1, we observed particularly high LSD1 protein expression in ML-DS primary samples...Consequently, we tested LSD1i and Ruxolitinib in a PDX-based murine ML-DS model, where the combination led to a significant reduction in blast count compared to monotherapies and control group....We identified LSD1i in combination with disruption of JAK-STAT signaling by Ruxolitinib as potential new treatment strategy in ML-DS with efficacy in vitro and in vivo.