NOTCH1 and MYC regulate leukemia cell growth. Activation of NOTCH1 signaling in T-ALL is typically triggered by activating mutations in the NOTCH1 gene and loss of function mutations in FBXW7. NOTCH1 directly activates MYC expression via NMe, a long-range NOTCH-dependent T-cell–specific enhancer duplicated in about 5% of T-ALLs. Chromosomal translocations involving MYC can also be found in 1% of T-ALLs, and FBXW7 mutations contribute to activating MYC expression by stabilizing the MYC protein. NOTCH1 and MYC regulate common transcriptional targets in a feed-forward loop circuitry that promotes leukemia cell growth, proliferation, and self-renewal.