Aberrant Notch signaling has been implicated in the development of several diseases, including T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder that originates from hematopoietic precursors committed to T-cell lineage. Survival rates in T-ALL patients have greatly improved in the last decades but still a substantial number of patients will relapse and die. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and 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. UPR is a conserved adaptive signaling pathway which tries to restore protein homeostasis mainly after Endoplasmatic Reticulum (ER) stress. It has been demonstrated that cancer cells are able to maintain malignancy by acquiring therapy resistance through its UPR signaling. Since several mutations of Notch3 protein have been recently identified, our main aim is to evaluate the role of Notch3 (N3) in sustaining UPR signaling in N3-overexpressing T-ALL cell lines.
The therapy of T-ALL patients has gradually improved in recent decades. Since UPR is activated in a wide variety of tumor types and it has been demonstrated to be essential for tumor cell survival, this conserved adaptive signaling pathway is gaining increasing recognition as a key targetable pathway1. The therapeutic potential of targeting UPR signaling in cancer could involve two approaches: 1. inhibition of UPR to eliminate tumors that are strongly dependent on an activated UPR for their survival in unfavorable conditions (highly stressed ER) or 2. induction of accumulation of misfolded protein in ER by pharmacological agents, in order to overload restoration ability of tumor with compromised UPR1. The role of UPR in acute leukemia subsets has only recently begun to be elucidated; in particular, it remains to be elucidated more in details how different oncogenes are able to influence the UPR autonomously or through interaction with the ER sensors, raising the possibility to the identification of new selective therapeutic opportunity for future treatment of T-ALL.
In this scenario, the aims of this study are: 1. to evaluate whether the absence of Notch3 might interfere in the ability of leukemic cells to adequately respond to ER stress by properly activating UPR signaling; 2. to investigate the molecular mechanisms involved in Juglone-induced cell death which is worthy, in order to limit the lymphocyte-related adverse effects2, finally retaining the antitumor effectiveness of this quinone.
Our findings will provide a rationale for the use of Notch3 inhibitors and Juglone-based combination protocols in the treatment of a subset of T-ALLs, as Juglone-induced apoptotic effects could be significantly amplified by Notch3- dependent UPR perturbation, thus finally suggesting a more selective novel strategy that could ameliorate the side-effects of the current treatments.
References
1.Tameire et al, 2015; 2.Seshadary et al, 2011.