Loss of T-cell quiescence by targeting Slfn2 prevents the development and progression of T-ALL.

// Aviya Goldshtein 1 , Shani Mistriel Zerbib 1 , Ibrahim Omar 1 , Leonor Cohen-Daniel 1 , Daniel Popkin 2 and Michael Berger 1 1 The Lautenberg Center for Immunology and Cancer Research, The Biomedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School Jerusalem, Israel 2 Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA Correspondence to: Michael Berger, email: // Keywords : T-cell quiescence, T-ALL, Schalfen2, Notch1, p53 Received : April 11, 2016 Accepted : April 26, 2016 Published : May 17, 2016 Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Despite significant improvement in the treatment of T-ALL, approximately 20% of children and most adults undergo relapse. Previous findings demonstrated that loss of T-cell quiescence due to a mutation in the Slfn2 gene ( elektra ) leads to acquisition of an aberrant developmental program by which T-cells lose their renewal capabilities and undergo apoptosis. Here we show that the elektra mutation in Slfn2 completely prevents a severe lymphoproliferative disease caused by overexpression of BCL2 in combination with Fas deficiency in mice. Moreover, Slfn2 impaired-function protects mice from experimental disease similar to human T-ALL by severely impairing the proliferation potential and survival of leukemic T-cells, partially by activation of the p53 tumor suppressor protein. Our study suggest that in certain malignancies, such as T-ALL, a novel therapeutic strategy may be applied by imposing aberrant development of leukemic cells. Furthermore, as the elektra mutation in Slfn2 seems to impair only T-cells and monocytes, targeting Slfn2 is expected to be harmless to other cell types, and thereby could be a promising target for treating malignancies. Together our results demonstrate the potential of targeting Slfn2 and its human paralog for T-ALL treatment.