title: A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.
abstract: Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ortega
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Bhatnagar
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: A-P
authors.initials: AP
authors.lastname: Lin
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Sill
authors.affiliation: 1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [3] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA [4] South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, USA.
authors.forename: R C T
authors.initials: RC
authors.lastname: Aguiar
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: C546086:MIRN30b microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D008156:Luciferases