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Expression profile of small nucleolar RNA (snoRNA) in acute myeloid leukemia.

ABSTRACT: Leukemogenesis requires enhanced self-renewal activity, which is induced by specific oncogenes. The underlying molecular mechanisms remain incompletely understood. We transduced mouse lineage negative bone marrow cells (enriched for hematopoietic stem and progenitor cells) with retrovirus expressing leukemic oncogene AML1-ETO9a, MYC and MLL-AF9 as well as empty vector (MIG). We found that all three oncogenes enhanced snoRNA formation. High abundance of snoRNAs was observed in primary human AML specimens with the notable exception of NPM1 mutant AML. Leukemogenesis by AML1-ETO required expression of the groucho related Amino Enhancer of Split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, loss of C/D box snoRNAs with concomitant loss of rRNA 2’-O-methylation resulted in decreased leukemia self-renewal potential.In summary, we identified C/D box snoRNAs and rRNA 2’-O-methylation as critical determinants of leukemic stem cell activity.

OTHER RELATED OMICS DATASETS IN: PRJNA378224PRJNA319473PRJNA319363PRJNA319361PRJNA319190PRJNA319362

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE80523 | GEO | 2017/06/20

SECONDARY ACCESSION(S): PRJNA319190

REPOSITORIES: GEO

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Similar Datasets

Expression data from AML1-ETO9a mouse primary leukemia blast

Project description:Microarray gene profilling indentified snoRNAs are downstream target of Amino Enhancer of Split (AES) and are essential for AML1-ETO9a induced leukemia. Amino Enhancer of Split (Aes) is strongly induced by leukemia oncogenes AML1-ETO, PML-RARα and PLZF-RARα. With a conditional AES knockout mouse model we showed that AES is essential for AML1-ETO9a indeced leukemia. We performed gene expression microarray using mouse primary AML1-ETO9a transformed AES wildtype and knockout and showed that snoRNAs were downregulated in AES knockout cells. We found that SnoRNA induction is a common mechanism shared by distinct oncogenes including AML1-ETO, MYC and MLL-AF9. Suppression of C/D box snoRNA complexes or deletion of several single C/D box snoRNAs inhibit clonogenic growth of leukemia cells. These findings suggest that enhancement of snoRNA levels is a critical mechanism of leukemic transformation.

2017-06-20 | GSE80579 | GEO

Expression profile of small nucleolar RNA (snoRNA) in human acute myeloid leukemia with different leukemia stem cell frequency

Project description:Leukemogenesis requires enhanced self-renewal activity, which is induced by specific oncogenes. The underlying molecular mechanisms remain incompletely understood. We measured snoRNA expression in human primary AML samples that contained determined leukemia stem cells frequency. We identified that expression of C/D box snoRNAs was closely associated with leukemia stem cell frequency.

2017-06-20 | GSE95721 | GEO

2'O-methylation profile of ribosomal RNA in Kasumi-1 SNORD42A knock out cells by RiboMethSeq

Project description:Non-coding RNAs including small nucleolar RNAs (snoRNAs) play important roles in leukemogenesis but the relevant mechanisms remain incompletely understood. We performed snoRNA focused CRISPR-Cas9 knockout library screenings which targeted the entire snoRNAnome and corresponding host genes. The C/D box containing SNORD42A was identified as an essential modulator for AML cell survival and proliferation in multiple human leukemia cell lines. In line, SNORD42A was consistently expressed at high levels in primary AML patient samples. Functionally, knockout of SNORD42A reduced colony formation capability and inhibited proliferation. The SNORD42A acts as a C/D box snoRNA and directs 2´-O-methylation at Uridine 116 of 18S rRNA. Deletion of SNORD42A decreased 18S-U116 2´-O-methylation which was associated with a specific decrease in the translation of ribosomal proteins. In line, the cell size of SNORD42A deletion carrying leukemia cells was decreased. Taken together, these findings establish that high level expression of SNORD42A with concomitant U116 18S rRNA 2´-O-methylation is essential for leukemia cell growth and survival.

2020-02-25 | GSE140355 | GEO

Identification of Amino Enhancer of Split (AES) and DDX21 binding snoRNAs by RIP-Seq.

Project description:We studied AES and DDX21 binding RNAs in Kasumi-1 cells stably expressing V5-tagged AES. RNA immunoprecipitation was performed with V5 antibody (for AES), DDX21 antibody and control IgG. We found that AES as well as DDX21 RIP samples showed enrichment for small nucleolar RNAs (snoRNAs) compared to control IgG. We also showed that AES and DDX21 binding snoRNAs showed significant overlap. Our studies provide mechanisms how AES regulates snoRNAs and rRNA modification.

2017-06-20 | GSE80581 | GEO

Nascent RNA-seq in Kasumi-1 cells

Project description:Amino Enhancer of Split (AES) is essential for AML1-ETO induced self-renewal and leukemogenesis. To study the effect of AES on transcription regulation in AML1-ETO expressing Kasumi-1 cells, nascent transcripts in control (shctr) and AES knockdown (shAES) Kasumi-1 cells were labelled with uridine analogue 4-thioduridine with subsequent nascent RNA purification and next generation sequencing (Nascent RNA-seq).

2017-06-20 | GSE80582 | GEO

Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

Project description:The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AETFC, that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO–expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO–expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite overlapping to some extent, the three E proteins differentially regulate many target genes, and, in particular, that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO–mediated leukemogenesis, E2-2 compromises the function of AETFC and acts as a negative regulator of leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.

2018-12-14 | GSE114644 | GEO

Next generation sequencing identifies discrete classes of box C/D snoRNAs featuring different ends and RNA binding protein dependency

Project description:The paired-end next-generation sequencing of all small RNAs of less than 200 nucleotides in length from four different human cell lines (SKOV3ip1, MCF-7, BJ-Tielf, INOF) allowed us to determine the exact sequence(s) and variations of human box C/D snoRNAs (small nucleolar RNAs), revealing processing patterns of this class of molecules. Two distinct groups of box C/D snoRNAs were identified based on the position of their ends with respect to their characteristic boxes and the terminal base pairing potential. Short box C/D snoRNAs start sharply 4 or 5 nucleotides upstream of their box C and end 2 or 3 nucleotides downstream of their box D. In contrast, long box C/D snoRNAs start 5 or 6 nucleotides upstream of their box C and end 4 or 5 nucleotides downstream of their box D, increasing the likelihood of formation of a k-turn between their boxes C and D. Sequencing of SKOV3ip1 cells following the depletions of NOP58, a core box C/D snoRNA-binding protein and of RBFOX2, a splicing factor, shows that the short box C/D snoRNA forms are significantly more affected by the depletion of RBFOX2 while the long snoRNA forms, which display more canonical box C/D snoRNA features, are significantly more affected by the depletion of NOP58. Together the data suggest that box C/D snoRNAs are divided into at least two groups of RNA with distinct maturation and functional preferences. Small RNAs (<200 nucleotides) were isolated from different human cell lines that were either untreated or depleted of NOP58 or RBFOX2 using specific siRNAs. The resulting libraries were multiplexed and paired-end sequenced using Illumina HiSeq.

2014-07-01 | E-GEOD-55946 | biostudies-arrayexpress

PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Project description:In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.

2021-11-04 | PXD026374 | Pride

Next generation sequencing identifies discrete classes of box C/D snoRNAs featuring different ends and RNA binding protein dependency

2014-07-01 | GSE55946 | GEO

Expression data from splenic B-cells isolated from DmU50(HG-b) mice or wild-type C57BL/6J

Project description:Box C/D-type small nucleolar RNAs (snoRNAs) are functional RNAs responsible for mediating 2’-O-ribose methylation of ribosomal RNAs (rRNAs) within the nucleolus. Previously, in relation to a novel chromosomal translocation in a human B-cell lymphoma, we identified U50HG, a non-protein-coding gene that hosted a box C/D-type U50 snoRNA within its intron. To investigate the physiological importance of the U50 snoRNA and its involvement in tumorigenesis, we generated a mouse model deficient in mouse U50 (mU50) snoRNA expression without altering the expression of mouse mU50 host-gene, mU50HG-b. The established mU50 snoRNA-deficient mice showed a significant reduction of mU50 snoRNA expression and the corresponding target rRNA methylation in various organs. Lifelong phenotypic monitoring showed that the mU50-deficient mice looked almost normal without accelerated tumorigenicity; however, a notable difference was the propensity for anomalies in the lymphoid organs. B-cells were isolated from spleens of DmU50(HG-b) mice or wild-type C57BL/6J with antibody-conjugated magnetic beads system (Myltenyi Biotec). Total RNA was purified with QIAGEN RNeasy Micro kit. Affymetrix GeneChip® Microarrays (Mouse Expression 430 2.0 Array) were used.

2013-03-26 | E-GEOD-41164 | biostudies-arrayexpress

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