NOTCH1 is a receptor that mediates signaling by numerous ligands and transcriptional factors in diverse cell contexts.1 In T-ALL, NOTCH1 mutations activate an oncogenic signaling cascade that is characterized by ligand-independent activation of the NOTCH1 receptor, which results in the aberrant induction of MYC, a key regulator of cell proliferation and survival. Aberrant NOTCH1 signaling induces Myc by direct transcriptional activation of the Myc promoter, by induction of the transcriptional repressor HES1, and by suppression of the Myc inhibitors p21 and the FOXO family transcription factor FOXO1. Notch1 signaling can also induce a broad transcriptional program that includes genes involved in cell metabolism.
NOTCH1 signaling is also important for T-ALL cell growth and proliferation by promoting cell size.2,100 Increased NOTCH1 activity in T-ALL cells promotes cell growth by downregulating the metabolism of glutamine and glucose and by increasing ribosome biogenesis.2,101-104 Notch1 activity also promotes cell survival by promoting the autophagic flux, thereby favoring cell turnover and cell growth.2,105,106 More recently, for instance, the Notch1-mediated transcription of the long noncoding RNA LUNAR has emerged as an important oncogenic mechanism in T-ALL.57,107
In the present study, we show that treatment of T-ALL cell lines with a small molecule that specifically inhibits the NOTCH1-mediated transcriptional activity of the HES1 transcription factor results in strong anti-proliferative and pro-apoptotic effects in T-ALL cells.
Next week we'll be revealing a new set of mods for Destiny 2 which are yet to be announced. It's time to cover off the most exciting part of any Destiny 2 update, the Mod World Update.
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