Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1.

• Main Authors: Rita Fragoso, Tin Mao, Song Wang, Steven Schaffert, Xue Gong, Sibiao Yue, Richard Luong, Hyeyoung Min, Yumi Yashiro-Ohtani, Mark Davis, Warren Pear, Chang-Zheng Chen
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC3415433?pdf=render

Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1.