AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia.
Fengbiao ZhouYi LiuChristian RohdeCornelius PauliDennis GerloffMarcel KöhnDanny MisiakNicole BäumerChunhong CuiStefanie GöllnerThomas OellerichHubert ServeMaria-Paz Garcia-CuellarRobert K SlanyJaroslaw P MaciejewskiBartlomiej PrzychodzenBarbara SeligerHans-Ulrich KleinChristoph BartenhagenWolfgang E BerdelMartin DugasMakoto Mark TaketoDaneyal FarouqSchraga SchwartzAviv RegevJosée HébertGuy SauvageauCaroline PabstStefan HüttelmaierCarsten Muller-TidowPublished in: Nature cell biology (2017)
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.
Keyphrases
- binding protein
- transcription factor
- stem cells
- acute myeloid leukemia
- poor prognosis
- end stage renal disease
- allogeneic hematopoietic stem cell transplantation
- ejection fraction
- dna methylation
- induced apoptosis
- chronic kidney disease
- peritoneal dialysis
- prognostic factors
- gene expression
- atrial fibrillation
- endoplasmic reticulum stress
- human health
- cell proliferation
- patient reported outcomes
- small molecule
- cell death
- cell therapy