title: Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia in a pre-clinical model.
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.
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Md Nabiul
authors: MN
authors: Hasan
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Manon
authors: M
authors: Queudeville
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Luca
authors: L
authors: Trentin
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Sarah Mirjam
authors: SM
authors: Eckhoff
authors: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors: Ilaria
authors: I
authors: Bronzini
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, University of Milano-Bicocca, Monza, Italy.
authors: Chiara
authors: C
authors: Palmi
authors: Institute for Pathology, Ulm University Medical Center, Ulm, Germany.
authors: Thomas
authors: T
authors: Barth
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, University of Milano-Bicocca, Monza, Italy.
authors: Giovanni
authors: G
authors: Cazzaniga
authors: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors: Geertruy
authors: G
authors: te Kronnie
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: Lüder Hinrich
authors: LH
authors: Meyer
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human