Journal Article

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

Göllner, Stefanie, Farouq, Daneyal, Przychodzen, Bartlomiej, Slany, Robert, Sauvageau, Guy, Hüttelmaier, Stefan, Misiak, Danny, Oellerich, Thomas, Taketo, Makoto Mark, Schwartz, Schraga, Pabst, Caroline, Zhou, Fengbiao, Liu, Yi, Berdel, Wolfgang E., Dugas, Martin, Maciejewski, Jaroslaw P., Seliger, Barbara, Pauli, Cornelius, Rohde, Christian, Gerloff, Dennis, Köhn, Marcel, Regev, Aviv, Serve, Hubert, Müller-Tidow, Carsten, Bartenhagen, Christoph, Garcia-Cuellar, Maria-Paz, Bäumer, Nicole, Hébert, Josée, Cui, Chunhong, Klein, Hans-Ulrich

2017

Overview

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. Zhou et al. show that in the context of AML1-ETO-driven leukaemia, AES and DDX21 induce small nucleolar RNA (snoRNA)–ribonucleoprotein (RNP) formation and this is important for self-renewal of leukaemic cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/100 / 13/109 / 13/31 / 13/44 / 13/89 / 14/63 / 38/23 / 38/39 / 38/61 / 631/337/384/521 / 631/67 / 631/67/395 / 64/60 / AML1 protein / Animals / Cancer cells / Cancer Research / Cell Biology / Cell Proliferation / Cell Self Renewal / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cell Transformation, Neoplastic - pathology / Clonal deletion / Core Binding Factor Alpha 2 Subunit - genetics / Core Binding Factor Alpha 2 Subunit - metabolism / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Development and progression / Developmental Biology / DNA helicase / Enhancer-of-split protein / Gene Expression Regulation, Leukemic / Genetic Predisposition to Disease / Growth / HEK293 Cells / HL-60 Cells / Humans / In vitro methods and tests / K562 Cells / Leukemia / Leukemia - genetics / Leukemia - metabolism / Leukemia - pathology / Life Sciences / Methylation / Mice, Inbred C57BL / Mice, Knockout / Molecular modelling / Myc protein / Myeloid-Lymphoid Leukemia Protein - genetics / Myeloid-Lymphoid Leukemia Protein - metabolism / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Phenotype / Protein Interaction Maps / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Repressor Proteins - genetics / Repressor Proteins - metabolism / Ribonucleic acid / Ribonucleoproteins - genetics / Ribonucleoproteins - metabolism / RNA / RNA helicase / RNA, Ribosomal - genetics / RNA, Ribosomal - metabolism / RNA, Small Nucleolar - genetics / RNA, Small Nucleolar - metabolism / rRNA / RUNX1 Translocation Partner 1 Protein / Signal Transduction / snoRNA / Stem Cells / Time Factors / Transcription Factors - genetics / Transcription Factors - metabolism / U937 Cells