GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.

1st Medical Department Hematology General Faculty Hospital Prague Czech Republic

Biocev and Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Biology University of Crete Heraklion Crete Greece

Institute of Hematology and Blood Transfusion Prague Czech Republic

Institute of Molecular Biology and Biotechnology Foundation of Research and Technology Hellas Heraklion Crete Greece

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