Acute leukemia is a hematological malignancy that arises either from the lymphoid cell lineage (acute lymphoblastic leukemia or ALL) or the myeloid cell lineage (acute myeloid leukemia or AML). This heterogenic disease is characterized by a clonal expansion and rapid accumulation of immature, nonfunctional white blood cells in the bone marrow. Based on the cytogenetic and molecular profile or response to induction therapy, patients can be stratified into favorable, intermediate and adverse-risk groups. But even with patient-specific intensified cytotoxic chemotherapy and stem cell transplantations, adult acute leukemia patients have a 5-year overall survival of only 25-35%, making it one of the more deadly and difficult to treat cancers. Recent large-scale functional screening in cancer cell lines have enabled the identification of a set of AML/ALL dependency genes as putative novel therapeutic targets. Most of these are encoding for transcription factors, including ZEB2 and RUNX2. Based on our data, we are convinced that temporal downregulation of their expression or perturbing the function of these oncogenic transcription factors could represent a novel therapeutic opportunity for acute leukemia patients that are currently confronted with a poor prognosis. However, according to conventional appraoches, transcription factors are considered as ‘undruggable’ and often seen as too risk-full candidates to be explored in the classical drug-discovery pipelines. Nevertheless, advances in the field, including the introduction of small-molecule protein-protein/DNA interaction (PPI/PDI) disruptors and proteolysis-targeted chimeras (PROTAC), have changed the definition of ’druggable’over the last years. These novel avenues pave the way for novel therapeutic strategies targeting transcription factors. The goal of this project is to further explore these technologies to specifically target the oncogenic transcription factor network in acute leukemia.