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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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.
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.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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