T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of thymocytes. Despite significant improvement in the treatment of T-ALL, approximately 20% of children and most adults succumb to resistant or relapsed disease. Our recent findings of a Schlafen-2 (Slfn2) mutant mouse, elektra, demonstrated that loss of T cell quiescence leads to acquisition of an aberrant developmental program by which T cells lose their renewal capabilities and undergo apoptosis. We now demonstrate that elektra mutation in Slfn2 completely prevents a severe lympho-proliferative disease caused by overexpression of BCL2 in combination with Fas deficiency in mice. These findings suggest that even T cells lacking the two main apoptotic pathways, the intrinsic pathway and the extrinsic pathway, must have intact Slfn2 to allow for proliferation and immortalization. Following these results we could demonstrate that Slfn2 loss-of-function protects mice from experimental disease similar to human T-ALL, by severely impairing the proliferation potential of pre-leukemic T cells. Our results identify a role for Slfn2 in the development of T-ALL through the regulation of the progression of pre-leukemic T cells to mature leukemic T cells.
