Much of our understanding of the biology of MYCN amplification in neuroblastoma is based on the exploration of transcriptional activity of MYCN. Powers and colleagues, in a paper in Nature, now show that MYCN RNA also has an important role in neuroblastoma in addition to MYCN protein production. Their findings place the Let-7 microRNA family front and centre in neuroblastoma biology.

As all roads lead to Rome, the oncogenic mechanisms in poor-prognosis neuroblastoma described in this paper converge on the repression of let-7 functions, of which the most important is the down-regulation of MYCN itself. It has been shown previously in neuroblastoma that let-7 expression is repressed by the LIN28B protein, which can bind the pri-miR let-7 (among other microRNAs) and prevent their processing into mature, active forms.3 As a starting point, Powers et al.2 have shown genetically that LIN28B is not required for repression of let-7 function in MYCN-amplified neuroblastoma cell lines. Instead, the abundant MYCN RNA is sufficient to soak up let-7 and still leave enough mRNA to be translated into elevated MYCN protein. This is a complex and unexpected oncogenic mechanism for a well-characterized oncogene, but the data are compelling. It also provides an explanation of at least one curious feature of MYCN biology in neuroblastoma. MYCN gene amplification has always been a more powerful marker of poor prognosis than was elevated MYCN protein expression itself, a fact that is at odds with the proposition that the most relevant function of a protein-coding gene is that of producing the protein. Furthermore, the selective pressure in favour of the often extraordinarily high copy number of MYCN genes in neuroblastoma has remained obscure. Now, Powers et al.2 have probably solved the puzzle. The amplification of MYCN copy number produces enough mRNA to effectively titrate down the amount of let-7. This breaks the negative feedback between let-7 and MYCN. MYCN protein produced in neuroblastoma cells is then derived from the MYCN mRNA not engaged with let-7 and that may significantly vary among tumours.

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