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Leukemia. 2017 Apr;31(4):853-860. doi: 10.1038/leu.2016.296. Epub 2016 Oct 24.

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

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Service des Maladies du Sang, CHRU Lille, Lille, France.
Jean-Pierre Aubert Research Centre, INSERM U1172, University Lille 2, Lille, France.
Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston MA, USA.
ASST Spedali Civili Department of Medical Oncology, CREA Laboratory, Brescia, BS, Italy.


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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