title: Loss of T-cell quiescence by targeting Slfn2 prevents the development and progression of T-ALL.
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.
authors.affiliation: 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.
authors.forename: Aviya
authors.initials: A
authors.lastname: Goldshtein
authors.affiliation: 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.
authors.forename: Shani Mistriel
authors.initials: SM
authors.lastname: Zerbib
authors.affiliation: 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.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Omar
authors.affiliation: 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.
authors.forename: Leonor
authors.initials: L
authors.lastname: Cohen-Daniel
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Popkin
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D018450:Disease Progression; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000073658:Loss of Function Mutation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D060168:Thymocytes / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C491899:Fas protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C521352:schlafen-2 protein, mouse; C052617:Bcl2 protein, mouse
keywords: Notch1; Schalfen2; T-ALL; T-cell quiescence; p53