Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia as a novel treatment strategy
Hasan, Md. Nabiul
Although intensification of chemotherapy regimens have improved the outcome of patients suffering from acute lymphoblastic leukemia (ALL) achieving cure rates of above 80 %, about 20 % of the patients encounter relapse which is associated with inferior outcome. By current strategies, the majority of relapse patients are not identified initially indicating the need for novel prognostic and therapeutic targets reflecting leukemia biology. Previously, we have described a strong association of leukemia cell engraftment of primary patient B cell precursor ALL samples transplanted into NOD/SCID/huALL mouse model and patient outcome. Rapid engraftment (time to leukemia, TTL short) is indicative for early patient relapse and associated with a gene expression profile pointing to mammalian target of rapamycin (mTOR) signaling which is involved in cell growth and proliferation. In this study, we 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. Using previously characterized xenografts, mTOR pathway activation was analyzed assessing phosphorylation of ribosomal protein S6 (p-S6), a molecule downstream of mTOR. Increased mTOR activation was found in TTL short/high-risk ALL, which was effectively abrogated by mTOR inhibitors resulting in decreased leukemia proliferation and growth ex vivo and also in vivo. 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 TTL short/high-risk ALL, but not in TTL long/late relapse ALL. Thus, TTL short/early relapse leukemia is functionally characterized by hyperactivated mTOR signaling which can be effectively targeted by mTOR inhibitors ex vivo and in vivo, thus providing a novel therapeutic strategy for the treatment of high-risk ALL.
Subject HeadingsAkute lymphatische Leukämie [GND]
Acute lymphoblastic leukemia, pediatric [MeSH]
Precursor cell lymphoblastic leukemia-lymphoma [MeSH]