Notch protection against apoptosis in T-ALL cells mediated by GIMAP5

Abstract

Recent studies have highlighted the role of Notch signalling in the development of T cell acute lymphoblasic leukaemia (T-ALL). Over-expression of Notch3 and gain of function mutations in the Notch1 gene have been reported. The aims of this study were to determine the effect of Notch signalling on apoptosis in human T-ALL cell lines and to identify targets of Notch signalling that may mediate this effect. Functional studies showed that inhibition of Notch signalling using gamma secretase inhibitors promoted glucocorticoid-induced apoptosis in cells carrying gain of function mutations in Notch1. Moreover, ectopic expression of constitutively activated Notch provided protection against glucocorticoid-induced apoptosis, indicating that signalling via Notch may also contribute to the development of T-ALL by conferring resistance to apoptosis. Microarray analysis revealed that GIMAP5, a gene coding for an anti-apoptotic intracellular protein, is upregulated by Notch in T-ALL cell lines. Knockdown of GIMAP5 expression using siRNA promoted glucocorticoid-induced apoptosis in T-ALL cells carrying gain of function mutations in Notch1 and in T-ALL cells engineered to express ectopic constitutively activated Notch indicating that Notch signalling protects T-ALL cells from apoptosis by upregulating the expression of GIMAP5.