Targeting the ER/UPR signalling in Notch3-overexpressing T-cell acute lymphoblastic leukemia.

Aberrant Notch signaling is involved in the development of several diseases, including T-cell acute lymphoblastic leukemia (T-ALL). A better knowledge of T-ALL biology has opened opportunities for the development of targeted therapies for the treatment of this disease. Recently, several studies suggest the role of the unfolded protein response (UPR) in acute leukemias. Juglone, a naturally-occurring naphtoquinone, is considered a promising anticancer agent for its strong activity against cancer cells in in vitro and in vivo models, including leukemia. Here we show the mechanism whereby Juglone induces apoptosis in T-ALL. Time course studies indicated that initial apoptotic events are driven by the inhibition of proteasome activity, which contributes to the induction of endoplasmic reticulum (ER) stress. Moreover, Juglone treatment induced Notch signalling down-regulation. Notably, Notch3 inhibition (but not Notch1) was able to amplify Juglone-induced T-ALL cell apoptosis through UPR perturbation, thus finally leading to a defective cell response to the prolonged Juglone-induced ER stress. Our findings provide a rationale for the use of Notch3 inhibitors and Juglone-based combination protocols in the treatment of a subset of T-ALLs, thus finally suggesting a more selective novel strategy that could ameliorate the side-effects of the current treatments.