Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4+ Infant ALL

Abstract

-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 -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 , by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 impairs the leukemic engraftment of patient-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of -rearrangedALL through the deregulation of , and gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoid-resistant -rearranged cells to prednisolone and is more efficient when used in combination with HDAC inhibitors, both and 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 -rearranged infant ALL for future clinical applications..

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

“…Earlier studies demonstrated also synergies of BRD inhibitors with other drugs, such as CBP/p300 inhibitors acting synergistically with BET inhibitors as well as cytotoxic agents and dexamethasone in leukemia 34 . In addition, BET inhibitors showed synergy in cancer models in combination with HDAC inhibitors 82–84 as well as kinase and PARP inhibitors 85–87 . The combination of different inhibitors might also be important in overcoming drug resistance which has been observed in cells treated with BET inhibitors 13 .…”

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

“…Recruitment of oxidative metabolism seems to also play a role in relapse in B-ALL (Dobson et al, 2020). We impaired MYC activity through inhibition of BET bromodomain proteins -an intervention that slows progression of MLL-driven leukemia -finding that this inhibitor blocked the conversion of CD34to CD34 + cells (Bardini et al, 2018;Dawson et al, 2011;Delmore et al, 2011). Together, our findings reinforce the notion that LICs are plastic and adaptable, providing possible explanations as to why therapies targeting LICs have yet to prove widespread efficacy despite being the object of intense investigation for over two decades (Pollyea and Jordan, 2017;Saygin et al, 2019).…”

Identification of hub genes and molecular mechanisms in infant acute lymphoblastic leukemia withMLLgene rearrangement

“…RUNX1 is known to be a putative target gene of MLL fusions, and was highly expressed in MLL-AF4 ALL cases, when compared with normal bone marrow cells (Guenther et al, 2008; Krivtsov et al, 2008). The BET inhibitor I-BET151, arrested the growth of MLL-AF4 infant leukemic cells in vitro through gene deregulation, including RUNX1 (Bardini et al, 2018).…”