c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.
By A. Weng, J. Millholland, Yumi Yashiro‐Ohtani, M. Arcangeli, A. Lau, C. Wai, Cristina Del Bianco, Carlos G. Rodriguez, Hong Sai, J. Tobias and 7 more. Genes & Development, 2006
931 citations recorded by the source corpus.
Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/22b35efb80b13a27c6afadcd2071a09dc91afdf2
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Citations in the corpus
- MYC on the Path to Cancer (2012, background): “MYC is downstream of deregulated Notch signaling pathways found in T cell leukemia (Palomero et al., 2006; Sharma et al., 2006; Weng et al., 2006).”
- Notch signalling in solid tumours: a little bit of everything but not all the time (2011, background): “MYC, a potent driver of cell cycle entry, is a direct transcriptional target of Notch and contributes to cell cycle progression in T-AL”