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

Abstract

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.

Expression signature of six‐snoRNA serves as novel non‐invasive biomarker for diagnosis and prognosis prediction of renal clear cell carcinoma

“…43 On the one hand, the C/D box snoRNAs exert a promotion role in tumorigenesis by regulating rRNA 2′-O-methylation. 44,45 SNORD12B and SNORD93 in our selected snoRNAs were C/D box snoRNAs and exhibited a tumorigenic effect in ccRCC. On the other hand, snoR-NAs exist methylation site and have poor prognosis in KIRC, so is snoRNA methylation correlated with better survival?…”

The snoRNA target of t(4;14) in multiple myeloma regulates ribosome biogenesis

“…34 Hence, our data led us to speculate that ACA11 overexpression stimulates the global translation initiation rates in MM cells, and increased protein synthesis necessary to support increased cell growth ( Figure 1B). 14 The tumor suppressor p53 also has been found to regulate the RNA methylase fibrillarin. Consistently, ACA11 knock down was followed by a decrease in both cell mass ( Figure 3D) and nascent protein synthesis per cell ( Figure 3E).…”

“…For example, C/D box snoRNAs and RNA 2′-O-methylation are critical for AML-ETO induced leukemia stem cell activity. 14 The tumor suppressor p53 also has been found to regulate the RNA methylase fibrillarin. 13 The precursor 45S is considered the unique steady state marker of transcription because the primary transcript pre-47S is rapidly processed.…”

“…8 High proliferation rates require increased protein synthesis, supported by upregulation of ribosome biogenesis pathways. [11][12][13][14][15] Interestingly in MM cells, ACA11 seems to interact with a small nucleolar ribonucleoprotein complex. 11 Post-transcriptional modifications (eg 2′-O-Ribose methylation and pseudouridylation) in ribosomal biogenesis are mainly regulated by two classes of snoRNAs, box C/D and box H/ACA, respectively, and have been implicated in cancer biology.…”

“…11 Post-transcriptional modifications (eg 2′-O-Ribose methylation and pseudouridylation) in ribosomal biogenesis are mainly regulated by two classes of snoRNAs, box C/D and box H/ACA, respectively, and have been implicated in cancer biology. [11][12][13][14][15] Interestingly in MM cells, ACA11 seems to interact with a small nucleolar ribonucleoprotein complex. 7 ACA11 physically interacts with nuclear proteins associated with RNA processing, including RNA splicing factors (SF3B1, SF3B2, and SFPQ), ATP-dependent RNA helicase A (DHX9), RNA-specific adenosine deaminase (ADAR), and eight members of the heterogeneous nuclear ribonucleoprotein family (HNRNP).…”