Activation of the Notch pathway occurs commonly in T acute lymphoblastic 
leukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the 
regulation of cell proliferation and survival. Deregulated Notch3 signalling has 
also been shown to promote leukemogenesis in transgenic mice, but the targets of 
Notch3 in human T-ALL cells remain poorly characterized. Here, we show that 
Notch3 controls levels of mitogen-activated protein kinase (MAPK) phosphatase 1 
(MKP-1). In a model of T-ALL cell dormancy, both Notch3 activation and MKP-1 
expression were upregulated in aggressive compared with dormant tumors, and this 
inversely correlated with the levels of phosphorylated p38 and extracellular 
signal-regulated kinase1/2 (ERK1/2) MAPKs, two canonical MKP-1 targets. We 
demonstrate that MKP-1 protein levels are regulated by Notch3 in T-ALL cell 
lines because its silencing by RNA interference or treatment with γ-secretase 
inhibitors induced strong MKP-1 reduction whereas activation of Notch3 
signalling had the opposite effect. Furthermore, MKP-1 has an important role in 
T-ALL cell survival because its attenuation by short hairpin RNA significantly 
increased cell death under stress conditions. This protective function has a key 
role in vivo, as MKP-1-deficient cells showed impaired tumorigenicity. These 
results elucidate a novel mechanism downstream of Notch3 that controls the 
survival of T-ALL cells.