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.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
Rita
R
Fragoso
Tin
T
Mao
Song
S
Wang
Steven
S
Schaffert
Xue
X
Gong
Sibiao
S
Yue
Richard
R
Luong
Hyeyoung
H
Min
Yumi
Y
Yashiro-Ohtani
Mark
M
Davis
Warren
W
Pear
Chang-Zheng
CZ
Chen
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
D035683:MicroRNAs; D051880:Receptors, Notch