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Anti-leukemic efficacy of BET inhibitor in a preclinical mouse model of MLL-AF4+ infant ALL.
Mol Cancer Ther. 2018 May 10;:
Authors: Bardini M, Trentin L, Rizzo F, Vieri M, Savino AM, Garrido Castro P, Fazio G, Van Roon EHJ, Kerstjens M, Smithers NN, Prinjha RK, Te Kronnie G, Basso G, Stam RW, Pieters R, Biondi A, Cazzaniga G
Abstract
MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein we have investigated the effects of BET function abrogation in a preclinical mouse model of MLL-AF4+ infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4+ leukemic cells in vitro, by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 in vivo impairs the leukemic engraftment of patients-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of MLL-rearranged ALL through the deregulation of BRD4, HOXA7/HOXA9 and RUNX1 gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoids-resistant MLL-rearranged cells to Prednisolone in vitro, and is more efficient when used in combination with HDAC inhibitors, both in vitro and in vivo. Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat MLL-rearranged infant ALL for future clinical applications.
PMID: 29748211 [PubMed - as supplied by publisher]
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