Het Transcriptionele Complex van TLX3 in T-cell Acute Lymfoblastische Leukemie

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the deregulation of developing T-cell progenitors. T-ALL is amongst other features characterized by the ectopic expression of transcription factors such as T-cell leukemia homeobox protein 3 (TLX3). To date, the exact oncogenic mechanism of TLX3 remains elusive. The host lab has recently developed in vitro mouse cell models and in vivo mouse leukemia models to study TLX3-driven leukemia development. Transcriptional profiling of these models has revealed the downregulation of multiple members of the transducin-like enhancer (TLE) family of transcriptional repressors of which TLE4 is also significantly downregulated in TLX3-positive human T-ALL cases. In the proposed project, I will first investigate how TLE4 influences the oncogenic function of TLX3 and if TLE4 is also able to regulate other transcription factors. To do so, I will use Chromatin Immunoprecipitation (ChIP-seq), CoIP and perform luciferase reporter assays. In addition, CRISPR/Cas9 knockdown will be used to test to which extent transcription factors regulated by TLE4 are crucial for leukemia development. Besides, I will also use a novel proximity biotinylation technique to characterize and validate the transcriptional complex of TLX3. The results of this project will contribute to a better understanding of transcriptional deregulation in cancer.