Gene expression-based chemical genomics identifies VPA to revert the oncogenic effect of GATA1s in Down syndrome leukemia

Children with Down syndrome (DS) are highly predisposed to acute myeloid leukemia (AML) and precedent transient leukemia (TL). For both malignancies mutations of the transcription factor GATA1 leading to the translation of the truncated variant GATA1s are a crucial event in the pathogenesis, but solitary insufficient for leukemogenesis. We compared global gene expression profiles of AML patient samples with and without GATA1 s-mutation to gene expression profiles of different small molecules via connectivity map and discovered the HDAC inhibitor valproic acid (VPA) to have the opposite effect on gene regulation…