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

Aviya Goldshtein,Michael Berger,Ibrahim Omar,Leonor Cohen-Daniel,Shani Mistriel Zerbib,Daniel Popkin

doi:10.18632/oncotarget.9390

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.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes
We demonstrate that Slfn2 is critical in the pathogenesis of T-ALL induced by intracellular domain of NOTCH1 (ICN1) and that downregulating Slfn2 attenuates the development and the progression of this disease
While BCL2(Tg)/FasIpr/lpr/Slfn2wt/eka mice showed enhanced lymphadenopathy and had a significantly larger number of cells in lymph nodes compared with control littermates that had an intact Fas (BCL2(Tg)/Faswt/lpr/Slfn2wt/eka), none of the abnormalities were observed in BCL2(Tg)/FasIpr/lpr/ Slfn2eka/eka mice (Figure 1d), suggesting that even T-cells lacking the two main apoptotic pathways dependent on BCL2 and FAS, must have an intact Slfn2 gene to support T-cell proliferation, immortalization and subsequent development of lymphadenopathy, thereby implying that Slfn2 may have a role in T-cell malignancies such as T-ALL

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. T-ALL is thought to result from malignant thymocytes that arise at defined stages during intrathymic T-cell differentiation [2]. NOTCH1 is activated by ligand binding, followed by its proteolytic cleavages that liberate the intracellular domain of NOTCH1 (ICN1) in the cytoplasm. The vast majority of these mutations occur in two domains: the extracellular domain, which lead to ligand-independent activation of NOTCH1, and/or the intracellular domain in the PEST subdomain, which cause enhanced ICN1 activity by www.impactjournals.com/oncotarget increasing its stability. Hyperactive NOTCH1 mutant alleles as well as ICN1 overexpression, in both human and mice bone marrow (BM) cells, lead to induction of T-ALL [3]

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