Priority Research Papers:
Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia in a pre-clinical model
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Md. Nabiul Hasan1, Manon Queudeville1, Luca Trentin1, Sarah Mirjam Eckhoff1, Ilaria Bronzini2, Chiara Palmi3, Thomas Barth4, Giovanni Cazzaniga3, Geertruy te Kronnie2, Klaus-Michael Debatin1 and Lüder Hinrich Meyer1
1 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
2 Department of Women’s and Children’s Health, University of Padova, Padova, Italy
3 Centro Ricerca Tettamanti, Clinica Pediatrica, University of Milano-Bicocca, Monza, Italy
4 Institute for Pathology, Ulm University Medical Center, Ulm, Germany
Lüder Hinrich Meyer, email:
Keywords: Acute lymphoblastic leukemia, pediatric, xenograft model, mTOR hyperactivation, preclinical targeting
Received: September 03, 2014 Accepted: December 01, 2014 Published: December 02, 2014
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.
Md. Nabiul Hasan
Sarah Mirjam Eckhoff
Geertruy te Kronnie
Lüder Hinrich Meyer
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