Priority Research Papers:
Loss of T-cell quiescence by targeting Slfn2 prevents the development and progression of T-ALL
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Abstract
Aviya Goldshtein1, Shani Mistriel Zerbib1, Ibrahim Omar1, Leonor Cohen-Daniel1, Daniel Popkin2 and Michael Berger1
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.
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