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Ref Type Journal Article
PMID (29748211)
Authors Bardini M, Trentin L, Rizzo F, Vieri M, Savino AM, Garrido Castro P, Fazio G, Van Roon EHJ, Kerstjens M, Smithers N, Prinjha RK, Te Kronnie G, Basso G, Stam RW, Pieters R, Biondi A, Cazzaniga G
Title Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4+ Infant ALL.
Journal Molecular cancer therapeutics
Vol 17
Issue 8
Date 2018 08
URL
Abstract Text MLL-rearranged acute lymphoblastic leukemia (ALL) 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 bromodomain and extra-terminal (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 patient-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 glucocorticoid-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. Mol Cancer Ther; 17(8); 1705-16. ©2018 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A - AFF1 acute lymphoblastic leukemia sensitive I-BET151 Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with I-BET151 in acute lymphoblastic leukemia cell lines harboring a KMT2A-AFF1 fusion resulted in growth inhibition, cell cycle arrest, increased apoptosis, and down-regulation of BRD4 targets CDK6, c-MYC, and BCL2 in culture, and resulted in reduced leukemic engraftment and decreased disease burden in a patient-derived xenograft (PDX) model and prolonged survival and reduced cellularity in a cell line xenograft model (PMID: 29748211). 29748211
KMT2A - AFF1 acute lymphoblastic leukemia predicted - sensitive I-BET151 + Panobinostat Preclinical - Cell line xenograft Actionable In a preclinical study, acute lymphoblastic leukemia cell line xenograft models harboring a KMT2A-AFF1 fusion treated with a combination therapy of I-BET151 and Farydak (panobinostat) demonstrated reduced cellularity and a prolonged survival of 34 days compared to 28 days for mice receiving either I-BET151 alone or 21 days for those treated with control (PMID: 29748211). 29748211
KMT2A - MLLT1 acute lymphoblastic leukemia predicted - sensitive I-BET151 + Prednisolone Preclinical - Cell culture Actionable In a preclinical study, treatment with I-BET151 enhanced the efficacy of Omnipred (prednisolone) in acute lymphoblastic leukemia cells harboring a KMT2A-MLLT1 (also known as MLL-ENL) fusion, resulting in increased cell death compared to either therapy alone in culture (PMID: 29748211). 29748211
KMT2A - AFF1 acute lymphoblastic leukemia predicted - sensitive I-BET151 + Prednisolone Preclinical - Cell culture Actionable In a preclinical study, treatment with I-BET151 enhanced the efficacy of Omnipred (prednisolone) in acute lymphoblastic leukemia cells harboring a KMT2A-AFF1 (also known as MLL-AF4) fusion, resulting in increased cell death compared to either therapy alone in culture (PMID: 29748211). 29748211
KMT2A - AFF1 acute lymphoblastic leukemia predicted - sensitive Givinostat + I-BET151 Preclinical - Cell culture Actionable In a preclinical study, combination therapy of I-BET151 and Givinostat (ITF2357) in acute lymphoblastic leukemia cell lines harboring a KMT2A-AFF1 fusion resulted in either a synergistic or additive effect, demonstrating increased apoptosis compared to either therapy alone in cell culture (PMID: 29748211). 29748211