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Multiple Myeloma, Gammopathies

The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma

Leukemia volume 31, pages 853–860 (2017)Cite this article

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Abstract

MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.

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Acknowledgements

SM was supported by a grant from ARC Foundation. This work was supported by a grant from the National Cancer Institute (R01CA154648). Author Information: RNA-sequencing data have been deposited to the Gene Expression Omnibus under accession numbers GSE71100.

Author contributions

SM, JTP, GQD and IMG designed research; SM, AS, SVG, DH, MRR and YM performed in vitro research; SM, KS and MM performed in vivo research; JS processed RNA-sequencing data; SM, JTP, CR-L, XL, AMR, GQD and IMG analyzed data; SM, JTP, SVG, GQD and IMG wrote the paper.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    S Manier, A Sacco, S V Glavey, D Huynh, M R Reagan, K Z Salem, M Moschetta, J Shi, Y Mishima, A M Roccaro & I M Ghobrial

  2. Service des Maladies du Sang, CHRU Lille, Lille, France

    S Manier & X Leleu

  3. Jean-Pierre Aubert Research Centre, INSERM U1172, University Lille 2, Lille, France

    S Manier & C Roche-Lestienne

  4. Division of Pediatric Hematology/Oncology, Children’s Hospital, Harvard Medical School, Boston, MA, USA

    J T Powers & G Q Daley

  5. ASST Spedali Civili Department of Medical Oncology, CREA Laboratory, Brescia, BS, Italy

    A Sacco & A M Roccaro

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  1. S Manier
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Correspondence to I M Ghobrial.

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Manier, S., Powers, J., Sacco, A. et al. The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma. Leukemia 31, 853–860 (2017). https://doi.org/10.1038/leu.2016.296

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