Manier, SalomonPowers, John T.Sacco, AntonioGlavey, Siobhan V.Huynh, DaisyReagan, Michaela R.Salem, Karma Z.Moschetta, MicheleShi, JiantaoMishima, YujiRoche-Lestienne, CatherineLeleu, XavierRoccaro, Aldo M.Daley, GeorgeGhobrial, Irene2017-05-012016Manier, S., J. T. Powers, A. Sacco, S. V. Glavey, D. Huynh, M. R. Reagan, K. Z. Salem, et al. 2016. “The LIN28B/let-7 axis is a novel therapeutic pathway in Multiple Myeloma.” Leukemia 31 (4): 853-860. doi:10.1038/leu.2016.296. http://dx.doi.org/10.1038/leu.2016.296.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630451MYC 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 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.en-USJournal Article2017-05-0110.1038/leu.2016.296