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

• Published in: Oncotarget 2016-07, Vol.7 (30), p.46835-46847
• Main Authors: Goldshtein, Aviya, Zerbib, Shani Mistriel, Omar, Ibrahim, Cohen-Daniel, Leonor, Popkin, Daniel, Berger, Michael
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Apoptosis; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Survival; Disease Progression; Down-Regulation; fas Receptor - genetics; HEK293 Cells; Humans; Leukemia, Experimental - metabolism; Leukemia, Experimental - pathology; Leukemia, Experimental - therapy; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy - methods; Monocytes - metabolism; Monocytes - pathology; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Priority Research Paper; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptor, Notch1 - metabolism; Resting Phase, Cell Cycle; Thymocytes - metabolism; Thymocytes - pathology; Transduction, Genetic; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9390

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.