Abstract
Despite increasingly successful treatment of pediatric ALL, up to 20% of patients encounter relapse. By current biomarkers, the majority of relapse patients is initially not identified indicating the need for prognostic and therapeutic targets reflecting leukemia biology. We previously described that rapid engraftment of patient ALL cells transplanted onto NOD/SCID mice (short time to leukemia, TTLshort) is indicative of early patient relapse. Gene expression profiling identified genes coding for molecules involved in mTOR signaling to be associated with TTLshort/early relapse leukemia. Here, we now functionally address mTOR signaling activity in primograft ALL samples and evaluate mTOR pathway inhibition as novel treatment strategy for high-risk ALL ex vivo and in vivo. By analysis of S6-phosphorylation downstream of mTOR, increased mTOR activation was found in TTLshort/high-risk ALL, which was effectively abrogated by mTOR inhibitors resulting in decreased leukemia proliferation and growth. In a preclinical setting treating individual patient-derived ALL in vivo, mTOR inhibition alone, and even more pronounced together with conventional remission induction therapy, significantly delayed post-treatment leukemia reoccurrence in TTLshort/high-risk ALL. Thus, the TTLshort phenotype is functionally characterized by hyperactivated mTOR signaling and can effectively be targeted ex vivo and in vivo providing a novel therapeutic strategy for high-risk ALL.
Highlights
Despite increasingly successful treatment of pediatric Acute lymphoblastic leukemia (ALL), up to 20% of patients encounter relapse
Based on our data pointing to critical involvement of mTOR signaling in TTLshort/high-risk leukemia, we addressed mTOR pathway activity by investigating phosphorylation of key signaling molecules: ribosomal protein S6 (S6), a downstream molecule which is phosphorylated by the ribosomal protein S6 kinase (p70S6K1) upon mTOR activation; and AKT, an upstream signaling kinase that is activated by phosphatidylinositol
We identified that in vivo proliferation of patient leukemia cells transplanted onto NOD/SCID mice is indicative of poor patient outcome and characterized by a specific transcript profile including genes coding for molecules regulating cell survival [6]
Summary
In about 20% of patients resulting in relapse associated with inferior prognosis, especially if the disease reoccurs at early time points [2]. The majority of patients encountering relapse are not identified by currently established prognostic markers including detection of minimal residual disease (MRD), but are initially stratified into standard- or intermediate risk groups [3, 4] These limitations clearly highlight the need for additional treatment modalities including improved risk stratification and novel therapies directed against identified targets. Treatment has become increasingly successful leading to five-year event-free survival rates of more than 80% This success is based on the use of risk adapted multi-agent chemotherapy protocols in which patients are assigned to therapy regimens with different intensities according to the individual probability to relapse [1]. Despite these major achievements in treatment of pediatric ALL, therapy fails www.impactjournals.com/oncotarget
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