Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

Abstract

Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments.

Targeting mTOR for the treatment of B cell malignancies

“…Notably, these mutations are strongly associated with poorer outcomes in both children and adults . Empirical evidence has also shown a direct correlation between AKT and/or mTOR activation and poor prognosis in patients with paediatric and adult B‐ALL .…”

mTOR signaling: new networks for ALL

“…1 m TOR signaling is elevated in both T-cell and B-cell ALL and correlates with high risk of relapse and resistance to chemotherapy regimens. 2 targeted agents. 5,6 However, the mechanisms by which mTOR dual inhibitors promote ALL cell death have not been established.…”

mTORC signaling in hematopoiesis

“…Elevated mTOR signaling was reported to correlate with poor prognosis in B-ALL patients [75]. However, no knockout mouse disease models for mTORC1 or mTORC2 to study B-ALL in mice was reported.…”