Powers, John T.Tsanov, Kaloyan MPearson, DanielRoels, FrederikSpina, Catherine SEbright, RichardSeligson, Marcde Soysa, YvankaCahan, PatrickTheiβen, JessicaTu, Ho-ChouHan, A ReumKurek, Kyle CLaPier, Grace SOsborne, JihanRoss, Samantha JCesana, MarcellaCollins, JamesBerthold, FrankDaley, George2017-02-182016Powers, J. T., K. M. Tsanov, D. S. Pearson, F. Roels, C. S. Spina, R. Ebright, M. Seligson, et al. 2016. “Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.” Nature 535 (7611): 246-251. doi:10.1038/nature18632. http://dx.doi.org/10.1038/nature18632.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:30371103Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.en-USJournal Article2017-02-1810.1038/nature18632