Oncogene coöperatie in T-cel acute lymfatische leukemie

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by the accumulation of genetic alterations that affect T-cell development. Gain-of-function mutations in NOTCH1, loss of the CDKN2A locus as well as chromosomal rearrangements resulting in dysregulated expression of T-cell-specific transcription factor genes constitute the most predominant alterations involved in the pathogenesis of T-ALL. Sequencing studies have shown that dysregulated expression of the TLX1 transcription factor often co-occurs with activating mutations in the IL7R/JAK/STAT signalling pathway. Conversely, TLX1 expression is rarely observed in combination with activation of other pathways, such as PI3K/Akt. In the proposed project, I will elucidate why dysregulated expression of TLX1 and activating IL7R mutations frequently co-occur, as well as how they interact and influence each other during T-ALL development. Using in vitro cultures of immature T-cells and in vivo mouse models, I will decipher the functions of and the mechanisms by which dysregulated TLX1 expression cooperates with constitutive activation of the IL7R pathway in driving T-ALL. The results forthcoming will provide novel insights in the functions and mechanisms of these cooperating oncogenic genetic alterations and might identify targets for the development of targeted anti-T-ALL therapy.

Publication year:2021

Accessibility:Open