T cell acute lymphoblastic leukaemia (T-ALL) is a common pediatric cancer that is frequently caused by the overexpression of transcription factors during T cell development. Our lab has identified the cellular origin of this disease in a mouse model of T-ALL in which the transcription factor LMO2 is overexpressed in the thymus. This gives rise to self-renewing thymocytes at the DN3 stage of development, referred as precancerous stem cells (pre-CSCs), that persist in the thymus for up to a year prior to leukaemia manifesting. Importantly, it has been shown that pre-CSCs are intrinsically resistant to treatment with gamma-irradiation, despite this killing over 99% of thymocytes. This intrinsic therapeutic resistance implicates pre-CSCs as a source of leukaemia relapse following therapy. In the current study, we have investigated the niche requirement of the pre- CSCs to develop better therapies to target these cells. In vitro experiments performed using OP9-DL1 culture system have indicated that as for normal DN3 cells, pre-CSCs can be maintained in vitro on feeder cells that express the Notch ligand Dll1, but not on cells that lack this factor, implying that Notch ligand are essential for pre-CSC survival and self-renewal. IL-7 titration experiments have shown that IL-7 cytokine is required for the growth of pre-CSCs in vitro. Moreover, thymocytes transplantation experiments performed using IL7-/- mice show that IL-7 is essential for the survival of pre-CSCs in vivo.
Together, these results indicate that pre-CSCs require the Notch and IL-7 signalling pathways, which may explain the high frequency of activating mutations in these pathways in T-ALL. Targeting these pathways could potentially yield the first targeted therapy to eliminate therapeutically resistant pre-CSCs during T-ALL treatment.