Research Summary

Investigation of aberrant TP53 regulation in Acute Lymphoblastic Leukaemia (ALL)

TP53 alterations are present in about 2-3% of children with acute lymphoblastic leukaemia (ALL) at initial diagnosis, but increases to ~13-15% at relapse and have been identified as the most significant subclonal mutation associated with recurrent therapeutic failure in ALL. These patients most often relapse early on-therapy. Another group of patients with similar clinical phenotype of early relapses, despite wild-type TP53, supports our hypothesis that common aberrant signalling pathways regulated either epigenetically in TP53 wild-type or by gain-of-function in TP53 altered ALL cells have an unexplored role in therapeutic failure. In addition, recent publications have offered insights into how the microenvironment influences cancer cell behavior and in turn is influenced by the cancer cells to create a favorable niche. One of our recent works has demonstrated how leukaemic cells can modulate the behavior of bone marrow stromal cells (BMSCs) resulting in altered mitochondrial metabolism in these stromal cells. p53 signaling pathways play a critical role in maintaining homeostasis of cells, especially with respect to mitochondrial metabolism and redox adaptation. We are yet to understand how the bone marrow stromal cells influence leukaemic cells with dysregulated p53 signaling or when harbouring TP53 alterations.


Figure Legend: Working hypothesis for the mechanism(s) by which TP53 alterations may contribute to chemoresistance and relapse in childhood acute lymphoblastic leukaemia.