KU Leuven

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease which arises from the malignant transformation of developing T-cell progenitors. It has a higher incidence in adult patients and while T-ALL is potentially curable with +-50% survival at 5 years, adult patients with relapsed disease have dreary outcomes with <10% of patients surviving long term, reflecting the importance of a better characterization of this disease. T-ALL is classified into distinct molecular subtypes based on different genetic profiles and stages of T cell development.

In this project we focus on one of T-ALL subtypes characterized by the ectopic expression of TLX1 protein, which belongs to the family of homeobox transcription factors, and it's found in 30% of adult T-ALL patients. Its normal function is poorly characterized since TLX1 its only known to be important for spleen development. In T-ALL, TLX1 becomes ectopically expressed in T-cell context and together with additional mutations drives T-ALL development.

Indeed, previous published data from our studies, showed cooperation of oncogenic transcription factor, TLX1, and signaling mutations (ABL1 and JAK/STAT signaling) in T-ALL. However, it is still unclear which additional transcriptional regulators are cooperating with TLX1 and how they regulate distinct signaling pathways that promote T-ALL proliferation. By performing screening assays that are currently being widely used in our laboratory, we first aim to identify TLX1 interacting partners.

Secondly, we will determine signaling pathways affected by the oncogenic cooperation between TLX1 and its interacting partners. Finally, we will test drug treatments against the most suitable target found in the previous steps. The feasibility of our approach is supported by our previous discoveries that demonstrate a great knowledge in the several proposed techniques. Altogether, our work is expected to have a positive translational impact by uncovering TLX1 oncogenic cooperation complex and like this clinically target an important effector that will result in killing a significant proportion of T-ALL found in adult patients.