A04: Loss of Y chromosome in acute myeloid leukemia drives tumorcell plasticity and drug resistance

Project A04 proposes that loss of KDM5D, a chromosome Y-specific histone H3 lysine-4 demethylase, associates with deficiencies in DNA repair and increases epigenetic and functional plasticity of human AML cells with mosaic loss of Y chromosome (mLOY). Using sc-multi omics approaches on engineered LOY iPSC/HSPC cells and primary patient samples as well as PDX mouse models A04 will analyze whether mLOY creates haploinsufficiency in epigenetic enzymes encoded on the Y chromosome, resulting in epigenomic heterogeneity of H3K4me3 and determine the impact of KDM5D/UTY/KDM6C loss on the functional plasticity of AML stem cells.