Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1172603 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30981152_1.fastq.gz | Fastqsanger.gz | |||
| SRR30981152_2.fastq.gz | Fastqsanger.gz | |||
| SRR30981153_1.fastq.gz | Fastqsanger.gz | |||
| SRR30981153_2.fastq.gz | Fastqsanger.gz | |||
| SRR30981154_1.fastq.gz | Fastqsanger.gz |
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Project description:NUP98 rearrangements associated with acute myeloid leukemia and myelodysplastic syndromes generate NUP98-fusion proteins. One such fusion protein, NUP98::DDX10, contains the putative RNA helicase DDX10. The molecular mechanism by which NUP98::DDX10 induces leukemia is not well understood. Here, we show that 24 amino acids within the DDX10 moiety of NUP98::DDX10 are crucial for cell immortalization and leukemogenesis. NOL10, nucleolar protein 10, interacts with the 24 amino acids, and NOL10 is a critical dependency of NUP98::DDX10 leukemia development. Studies in a mouse model of NUP98::DDX10 leukemia showed that loss of Nol10 impaired disease progression and improved survival. We also identified a novel function of NOL10 in that it acts cooperatively with NUP98::DDX10 to regulate serine biosynthesis pathways and stabilize ATF4 mRNA. Collectively, these findings suggest that NOL10 is a critical regulator of NUP98::DDX10 leukemia, and that targeting NOL10 (or the serine synthesis pathway regulated by NOL10) may be an effective therapeutic approach.
2025-03-31 | GSE279389 | GEO
Project description:Ribosomes, as a protein synthesis machine, are required for stem cells to maintain self-renewal. Here, we find that DEAD-box RNA helicase DDX10 is necessary for cellular pluripotency acquisition in somatic cell reprogramming, and in mouse embryonic stem cells (mESCs), DDX10 degradation disrupts cellular homeostasis, leads to cell cycle arrest in G1 phase and markedly inhibits cell proliferation. DDX10 is localized in dense fiber component (DFC) and granular component (GC), mainly binds to 45S ribosomal RNA (rRNA) and participates in regulating ribosome biogenesis. Specifically, DDX10 degradation prevents the release of U3 snoRNA from pre-rRNA, and disrupts pre-rRNA processing and maturation of 18S rRNA, leading to impaired ribosomal small subunit production. Together, this study reveals that DDX10 functions as an important regulator of ribosome biogenesis, and is essential for the survival, induction and maintenance of pluripotent stem cells.
2024-10-15 | GSE232093 | GEO
Project description:Ribosomes, as a protein synthesis machine, are required for stem cells to maintain self-renewal. Here, we find that DEAD-box RNA helicase DDX10 is necessary for cellular pluripotency acquisition in somatic cell reprogramming, and in mouse embryonic stem cells (mESCs), DDX10 degradation disrupts cellular homeostasis, leads to cell cycle arrest in G1 phase and markedly inhibits cell proliferation. DDX10 is localized in dense fiber component (DFC) and granular component (GC), mainly binds to 45S ribosomal RNA (rRNA) and participates in regulating ribosome biogenesis. Specifically, DDX10 degradation prevents the release of U3 snoRNA from pre-rRNA, and disrupts pre-rRNA processing and maturation of 18S rRNA, leading to impaired ribosomal small subunit production. Together, this study reveals that DDX10 functions as an important regulator of ribosome biogenesis, and is essential for the survival, induction and maintenance of pluripotent stem cells.
2024-10-15 | GSE232092 | GEO
Project description:We assessed lineage involvement by NUP98 translocations in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL). Single cell analysis by FICTION (Fluorescence Immunophenotype and Interphase Cytogenetics as a Tool for Investigation of Neoplasms) showed that NUP98-translocations with various partners, i.e. NSD1, DDX10, RAP1GDS1, and LNP1, always affected a CD34+/CD133+ hematopoietic precursor. Interestingly, in MDS/AML myelomonocytes, erythroid cells, B- and T- lymphocytes belonged to the abnormal clone, while in T-ALL only CD7+/CD3+ cells were involved. The partner did not appear to play a major role in determining the leukemia phenotype as shown in AML and T-ALL with the same NUP98-RAP1GDS1 fusion. Additional hits, namely mutations of FLT3 and CEBPA in MDS/AML and mutation of NOTCH1 plus MYB duplication in T-ALL, were identified in leukemias with, respectively, myeloid or T-lymphoid phenotype. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples. Copy number and Copy neutral LOH analysis of with Affymetrix Cytogenetic 2.7 and Cytoscan HD SNP arrays was performed on 6 NUP98 rearranged leukemias.
2014-08-26 | E-GEOD-60733 | biostudies-arrayexpress
Project description:Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in Acute Myeloid Leukemia (AML) with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has precluded the identification of efficient targeting strategies. We reasoned that shared transcriptional programs of direct NUP98-fusion-protein-mediated gene control converge on actionable targets. To study the transcriptional regulation mediated by NUP98 fusion proteins we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A and NUP98/DDX10. Integration of transcriptional changes after oncogene shutdown in vivo with ChIP-seq data identified a common core of direct NUP98-fusion target genes in AML. Among the direct targets of all NUP98-fusions, the CDK6 (cyclin-dependent kinase 6) gene was highly expressed in mouse and human AML samples. CDK6 loss severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was hypersensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing approved CDK4/CDK6 inhibitors as a rationale treatment option for AML patients with NUP98-fusions.
2020-05-08 | GSE134784 | GEO
Project description:We assessed lineage involvement by NUP98 translocations in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL). Single cell analysis by FICTION (Fluorescence Immunophenotype and Interphase Cytogenetics as a Tool for Investigation of Neoplasms) showed that NUP98-translocations with various partners, i.e. NSD1, DDX10, RAP1GDS1, and LNP1, always affected a CD34+/CD133+ hematopoietic precursor. Interestingly, in MDS/AML myelomonocytes, erythroid cells, B- and T- lymphocytes belonged to the abnormal clone, while in T-ALL only CD7+/CD3+ cells were involved. The partner did not appear to play a major role in determining the leukemia phenotype as shown in AML and T-ALL with the same NUP98-RAP1GDS1 fusion. Additional hits, namely mutations of FLT3 and CEBPA in MDS/AML and mutation of NOTCH1 plus MYB duplication in T-ALL, were identified in leukemias with, respectively, myeloid or T-lymphoid phenotype.
2014-08-26 | GSE60733 | GEO
Project description:RNA-binding proteins (RBPs) function in all steps of cellular RNA metabolism. Here, we find that Ddx10 gain-of-function promotes but loss-of-function impedes somatic cell reprogramming. Ddx10 loss-of-function results in significantly abnormal expression of innate immune response genes at the late stage of reprogramming. Knockdown of interferon transcription factor Irf1 or its downstream targets, Igtp and Tgtp2, respectively, obviously inhibited reprogramming. This study revealed that Ddx10 regulated reprogramming through modulating innate immune network.
2023-08-21 | GSE156610 | GEO
Project description:NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML), and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that histone acetyltransferase (HAT) complex proteins including MOZ associate with NUP98 FOs, and that BRPF1, an epigenetic writer that associates with MOZ is a molecular dependency in NUP98::KDM5A AML. Inactivation of Brpf1 as well as HAT complex member Moz, Hbo1, Brd1 or Meaf6 in Nup98::Kdm5a;Vav-Cre cells impaired fitness of NUP98-rearranged cells. MOZ inhibition decreased global H3K23ac levels, displaced FO from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ inhibition decreased leukemic burden in multiple NUP98-rearranged leukemia xenograft models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs. SIGNIFICANCE STATEMENT MOZ is a member of NUP98 FO condensates with key roles in leukemia phenotypes. MOZ inhibition is effective in multiple preclinical models, including those non-responsive to Menin inhibition. MOZ and Menin inhibition are synergistic in some NUP98-rearranged models, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.
2025-06-03 | PXD058286 | Pride
Project description:NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.
2020-12-23 | PXD022518 | Pride
Project description:The first genetic hits towards leukemia are thought often to confer to the mutant clone a slight proliferative/survial advantage. These pre-malignant clones can then be maintained under physiological cues in normal pool for long periods. We have searched for this type of first genetic hits and found that ectopic expression of novel nucleoporin 98 (NUP98)-homeodomain fusion proteins in primitive bone marrow cells can induce long-lasting hematopoietic stem cell (HSC) activity in these cells. More specifically, NUP98-CDX1/2 was able to sustain HSC activity with high frequencies despite massive in vitro expansions and in vivo residence. Continual expression of NUP98-CDX1/2 did not perturb lymphoid, myeloid or erythroid/platelet differentiation and NUP98-CDX1/2 was able to reprogram committed progenitors into cells with attributes of HSC. Switching off of NUP98-CDX1/2 expression did not lead to “return” to normal HSC but acute differentiation. Related NUP98-CDX4 induced leukemia with the shortest latency ever reported for HOX transcription factors. In this case switching off of NUP98-CDX4 expression cured the full-blown leukemia and again the cured cells showed only transient repopulating activity in vivo. These two types of pre-leukemic cells generated here will provide useful models for elucidating the self-renewal mechanisms of HSC as well as leukemic stem cells. Total RNA from NUP98-CDX lines was compared to EGFP overexpressing lines. The experiment was done in triplicate.
2012-12-01 | E-GEOD-37900 | biostudies-arrayexpress