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

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.
Author Summary Oncogenes elicit driving signals required for tumor initiation, development, and maintenance and are valuable targets for cancer therapy. However, oncogenes often have essential functions in normal cellular physiology and produce intracellular proteins that are difficult to inhibit with small molecule drugs without causing significant toxicity to normal tissues. Thus, one of the challenges in cancer therapy is to identify downstream networks that can be targeted to specifically dampen the oncogenic signals in tumor cells without harming normal tissues. In this study we demonstrate that deletion of a microRNA (miRNA) gene, mir-181a-1/b-1, specifically inhibits the activity of the Notch oncogene in tumorigenesis without causing significant defects in normal development. Although earlier studies have elegantly shown the essential role of NOTCH and pre-TCR signals in NOTCH-induced tumorigenesis, neither NOTCH nor pre-TCR signals can be targeted effectively for treatment of T-ALL with available drugs due to their weak therapeutic effects and severe toxicities. Our findings illustrate that dissecting the downstream targets of miRNAs can reveal the molecular networks that can be targeted to control tumor transformation caused by oncogenes. More importantly, our results illustrate that comparative studies on the pathways utilized by normal cells and tumor cells may reveal novel insights into how tumorigenic pathways may be selectively inhibited with limited damage to normal tissues.