XXX. (A) Synergy between each LSD1 inhibitor and ruxolitinib, with the greatest synergy between ORY-1001 and ruxolitinib (δ score, 22.028). To determine if there is synergy between LSD1 inhibition targeting SETBP1-driven pathways and a JAK1/2 inhibitor (ruxolitinib) targeting CSF3R-driven pathways, the CSF3R^T618I plus SETBP1^D868N cell line was plated in an 8 × 8 matrix in triplicate with increasing concentrations of each inhibitor. (B) RNA-seq data from cells treated with DMSO, 100 nM of ruxolitinib, 100 nM of GSK2879552 (GSK), 30 nM of ORY-1001, ruxolitinib with GSK2879552 (R+G), or ruxolitinib with ORY-1001 (R+O). Cluster 1 represents pathways upregulated more by the combination therapy than by either drug alone and includes a number of differentiation-associated transcription factors. Cluster 4 represents pathways downregulated more by the combination than by either drug alone and has an Myc and Fli1 signature. (C) Mice receiving transplants of the CSF3R^T618I plus SETBP1^D868N cell line were treated with 90 mg/kg of ruxolitinib twice per day and 0.75 mg/kg of GSK2879552 twice per day to determine if the combination treatment would improve survival over vehicle. Kaplan-Meier survival plot showing significant increase in survival with combination. (D) Mean mouse body weight during course of treatment with vehicle or combination. (E) Platelet counts at start of treatment (day 18) and midway through treatment course (day 27). Platelets did not decrease with combination treatment and remained within normal parameters. KD, knockdown; KO, knockout.