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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignant disease diagnosed in children, representing nearly one third of all pediatric malignancies
Our results raise an important question: what selection criteria should be used for identifying ALL patients who may benefit from Mammalian Target of Rapamycin (mTOR) inhibitors (MTIs) therapies? Should we decide based on resistance to chemotherapy, the occurrence of relapse, or high pre-treatment mTOR activity? We suggest that patients with poor prognosis may be identified by measuring p-4EBP1 levels at diagnosis; further markers will be required for predicting the potential response to rapamycin treatment for individual patients within this group
We determined the amount of mTOR activity related phosphoproteins in childhood ALL patients by ELISA
Summary
Acute lymphoblastic leukemia (ALL) is the most common malignant disease diagnosed in children, representing nearly one third of all pediatric malignancies. Several signal transduction pathways (PI3K/AKT/mTOR, JAK/STAT, ABL tyrosine kinase, SRC family of tyrosine kinases and NOTCH1) play a role in normal B- and T-cell development, proliferation, survival and activation [5]. Deregulation of these networks is likely to be a key event in leukemogenesis [7]. MTORC2 works in concert with PDK1 to phosphorylate/activate AKT; the function and regulation of mTORC2 and its response to rapamycin remains unclear, and may vary in different cell types [15,16] Activated mTORC1 phosphorylates two key translational regulators: eukaryotic initiation factor 4E binding protein (4EBP1) [13] and 70 kDa S6 ribosomal protein kinase (p70S6K) [14]. mTORC2 works in concert with PDK1 to phosphorylate/activate AKT; the function and regulation of mTORC2 and its response to rapamycin remains unclear, and may vary in different cell types [15,16]
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