title: The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma.
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.
authors: 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.
authors: S
authors: S
authors: Manier
authors: Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston MA, USA.
authors: J T
authors: JT
authors: Powers
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|ASST Spedali Civili Department of Medical Oncology, CREA Laboratory, Brescia, BS, Italy.
authors: A
authors: A
authors: Sacco
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: S V
authors: SV
authors: Glavey
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: D
authors: D
authors: Huynh
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: M R
authors: MR
authors: Reagan
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: K Z
authors: KZ
authors: Salem
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: M
authors: M
authors: Moschetta
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: J
authors: J
authors: Shi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Mishima
authors: Jean-Pierre Aubert Research Centre, INSERM U1172, University Lille 2, Lille, France.
authors: C
authors: C
authors: Roche-Lestienne
authors: Service des Maladies du Sang, CHRU Lille, Lille, France.
authors: X
authors: X
authors: Leleu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|ASST Spedali Civili Department of Medical Oncology, CREA Laboratory, Brescia, BS, Italy.
authors: A M
authors: AM
authors: Roccaro
authors: Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston MA, USA.
authors: G Q
authors: GQ
authors: Daley
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: I M
authors: IM
authors: Ghobrial
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D064593:Heterografts; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human