Cooperation of TLX3 with epigenetic changes in the development of T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer, which arises from the malignant transformation of developing T-cell progenitors. Genetic studies have identified a variety of chromosomal defects and point mutations that drive T-ALL development. TLX3 is a transcription factor that is frequently overexpressed in T-ALL. Interestingly, TLX3 expressing T-ALL cases often show inactivation of epigenetic factors such as CTCF, KDM6A or SMARCA4, while this is much less frequent in TLX3 negative cases. I hypothesize that the inactivation of CTCF, KDM6A or SMARCA4 cooperates with overexpression of TLX3 to drive leukemia development and progression. I will use ex vivo cultured T-cells and mouse leukemia
models to study the cooperation of TLX3 with inactivation of these epigenetic factors. I will also study the exact consequences of inactivation of CTCF, KDM6A or SMARCA4 on the chromatin structure and transcriptional activity of TLX3. In addition, I will use these models to identify
potential vulnerabilities in these leukemia cells that could serve as targets for therapy.