Format

Send to

Choose Destination
Oncotarget. 2016 Jul 26;7(30):46835-46847. doi: 10.18632/oncotarget.9390.

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

Author information

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.

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.

KEYWORDS:

Notch1; Schalfen2; T-ALL; T-cell quiescence; p53

PMID:
27206675
PMCID:
PMC5216906
DOI:
10.18632/oncotarget.9390
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center