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Lymphoma

A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies

Leukemia volume 29, pages 968–976 (2015)Cite this article

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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.

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Acknowledgements

We thank H Bouamar for technical help in generating the microRNA sponges, A Weng for suggestions and the Flow Cytometry Shared Resource Facility at UTHSCSA for the cell sorting. This work was supported by a grant from the National Cancer Institute (R01-CA138747), a Veterans Administration Merit Award (I01-BX001882) and a National Cancer Institute Cancer Center Support Grant (P30 CA054174).

Author Contributions

MO, HB, A-PL and LW designed and conducted the experiments and contributed to analysis; JCA provided reagents, contributed to analysis and gave conceptual advice; HS provided critical reagents, discussed experimental design and contributed to data analysis. RCTA conceived the project, designed the experimental strategy, conducted experiments, supervised the study and analysis and wrote the manuscript. All authors reviewed the manuscript and agreed to its content.

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Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    M Ortega, H Bhatnagar, A-P Lin, L Wang & R C T Aguiar

  2. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    J C Aster

  3. Division of Hematology, Medical University of Graz, Graz, Austria

    H Sill

  4. Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    R C T Aguiar

  5. Greehey Children’s Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA

    R C T Aguiar

  6. South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, USA

    R C T Aguiar

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  1. M Ortega
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  2. H Bhatnagar
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Correspondence to R C T Aguiar.

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Ortega, M., Bhatnagar, H., Lin, AP. et al. A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies. Leukemia 29, 968–976 (2015). https://doi.org/10.1038/leu.2014.302

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