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

Introduction: Acquired mutations in the hematopoietic transcription factor GATA1 (GATA1s), are consistently present in Down syndrome acute megakaryoblastic leukemia (DS-AMKL) and the antecedent transient leukemia. Truncated GATA1s fails to directly interact and repress E2F activators to coordinate proliferation and terminal megakaryocytic differentiation. Methods: To develop novel targeted and less toxic treatment options, we connected a DS-AMKL gene expression signature to a reference collection of gene-expression profiles from bioactive small molecules (Connectivity Map). Results: We discovered the histone dea…