AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia

作者：Zhou Fengbiao; Liu Yi; Rohde Christian; Pauli Cornelius; Gerloff Dennis; Koehn Marcel; Misiak Danny; Baeumer Nicole; Cui Chunhong; Goellner Stefanie; Oellerich Thomas; Serve Hubert; Garcia Cuellar Maria Paz; Slany Robert; Maciejewski Jaroslaw P; Przychodzen Bartlomiej; Seliger Barbara; Klein Hans Ulrich; Bartenhagen Christoph; Berdel Wolfgang E; Dugas Martin; Taketo Makoto Mark; Farouq Daneyal; Schwartz Schraga; Regev Aviv; Hebert Josee; Sauvageau Guy

来源：Nature Cell Biology, 2017, 19(7): 844-+.

DOI：10.1038/ncb3563

Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential. Genomic deletion of either C/D box snoRNA SNORD14D or SNORD35A suppressed clonogenic potential of leukaemia cells in vitro and delayed leukaemogenesis in vivo. We further showed that AML1-ETO9a, MYC and MLL-AF9 all enhanced snoRNA formation. Expression levels of C/D box snoRNAs in AML patients correlated closely with in vivo frequency of leukaemic stem cells. Collectively, these findings indicate that induction of C/D box snoRNA/RNP function constitutes an important pathway in leukaemogenesis.

• 出版日期2017-7
• 单位河北医科大学; MIT