Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core

We investigated the combination of the irreversible LSD1 inhibitor T-3775440 and the JAK1/JAK2 inhibitor ruxolitinib as novel therapeutic approach in ML-DS which is specifically designed to target key hallmarks of ML-DS leukemogenesis. We observed synergistic anti-leukemic effects by combining both drugs. To elucidate the underlying molecular mechanisms we performed RNAseq in two independent patients samples treated with vehicle, LSD1 inhibitor or ruxolitinib monotherapy or the combination of both drugs. Comparative gene expression profiling analysis of RNA-seq data for ML-DS samples of two different patients treated with DMSO, the LSD1 inhibitor T-3775440, ruxolitinib, or the combination of T-3775440 and ruxolitinib for 48 hours in vitro. Experiment was conducted with two replicates per condition.