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The NOTCH1-MYC regulatory circuit is particularly sensitive to inhibition of fatty acid and cholesterol metabolism. Cholesterol is a critical component of the plasma membrane and a potent activator of the oncogenic NOTCH-MYC circuit. The NOTCH1 receptor is synthesized as a precursor protein that undergoes maturation in the trans-golgi network before being expressed in the plasma membrane. After ADAM10 processing, the NOTCH1 ectodomain is transported to the plasma membrane by the Disabled-1-dependent internalization pathway, where it forms a NOTCH1-Hes1 dimer, which translocates into the nucleus and binds to the CSL DNA-binding protein. Assembly of the NOTCH1-RBPJ-CSL-MAML1 tetramer and a transcriptional complex leads to the activation of NOTCH target genes as well as to phosphorylation and proteolytic cleavage of MYC. MYC is highly unstable and is therefore targeted to the proteasome for degradation. On dimerization of NOTCH1 and transcriptional complexes, CSL-mediated Notch signaling results in inhibition of proteasome-mediated degradation of MYC, allowing for higher levels of nuclear MYC accumulation. Consequently, transgenic mice with active NOTCH1-dependent MYC signaling develop T-cell lymphoblastic leukemia with 100% penetrance at an average age of 26 weeks. This model is relevant for pre-T-ALL; however, most T-ALLs are derived from thymocytes with low to no NOTCH1 dysregulation. Hence, in most NOTCH1-mutant T-ALLs, the oncogenic activity of NOTCH1 is only transient and substantially low or absent.

Interestingly, NOTCH1-dependent T-ALLs are highly dependent on fatty acid and cholesterol metabolism for optimal cell growth. Fatty acids are the main cellular source of cholesterol. The inhibition of fatty acid synthesis results in induction of mitochondrial oxidative phosphorylation and a reduction in the intracellular accumulation of fatty acids, which leads to reduced fatty acid supply for lipid synthesis and loss of oncogenic activity of the NOTCH1-MYC circuit. The disruption of cholesterol metabolism is sufficient to induce T-cell leukemia with 100% penetrance and has been observed in T-ALL cells in vitro. d2c66b5586