Details

Autor(en) / Beteiligte

• Manier, S
• Powers, J T
• Sacco, A
• Glavey, S V
• Huynh, D
• Reagan, M R
• Salem, K Z
• Moschetta, M
• Shi, J
• Mishima, Y
• Roche-Lestienne, C
• Leleu, X
• Roccaro, A M
• Daley, G Q
• Ghobrial, I M

Titel

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

Ist Teil von

• Leukemia, 2017-04, Vol.31 (4), p.853-860

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.