Abstract
A NOTCH1-bound MYC enhancer is necessary for normal T-cell development and NOTCH1-induced T-ALL.
Major finding: A NOTCH1-bound MYC enhancer is necessary for normal T-cell development and NOTCH1-induced T-ALL.
Concept: NOTCH1 regulates MYC transcription by binding an intergenic enhancer that is amplified in T-ALL.
Impact: Disruption of NOTCH1-regulated MYC expression is a potential therapeutic strategy for T-ALL.
Activating NOTCH1 mutations occur in approximately 60% of human T-cell acute lymphoblastic leukemias (T-ALL) and are associated with activation of the MYC oncogene. However, the mechanisms that regulate MYC expression in NOTCH1-induced T-ALL are not well defined. Herranz and colleagues identified recurrent somatic duplications of an intergenic region at chromosome 8q24 downstream of the MYC oncogene in human T-ALL. This duplicated region exhibited enhanced binding of NOTCH1 and was associated with histone marks characteristic of active long-range super-enhancers in both human and mouse T-ALL cell lines. Further, this NOTCH1-bound MYC enhancer (N-Me) interacted with proximal regulatory sequences in the MYC promoter and stimulated MYC promoter activity in a NOTCH1-dependent and dose-dependent manner. Genetic knockout of the N-Me enhancer region in mice specifically resulted in a reduction in thymus size and cellularity, suggesting a role for N-Me in thymocyte development. Indeed, N-Me knockout mice exhibited reduced thymocyte proliferation, a decrease in mature CD4+ and CD8+ T cells, and accumulation of immature double-negative thymocytes with decreased MYC expression. Moreover, in a mouse model of T-ALL driven by constitutively active NOTCH1, loss of one copy of N-Me delayed leukemia development and homozygous deletion of N-Me prevented tumor formation, suggesting that N-Me is required for leukemia initiation. In addition, inducible knockout of N-Me in mice with established T-ALL extended survival and reduced the frequency of leukemia-initiating cells, implicating this super-enhancer in the maintenance of NOTCH1-driven T-ALL. Importantly, restoration of MYC expression in N-Me–deficient cells rescued both normal T-cell development and NOTCH1-driven tumor cell growth. Collectively, these studies characterize N-Me as an important NOTCH1-regulated enhancer that contributes to the development of T-ALL and may have implications for therapeutic strategies to disrupt NOTCH1-induced MYC expression in T-ALL.