Mutant NPM1 marginally impacts translation in AML cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE251919 | GEO | 2024/09/30
REPOSITORIES: GEO
Similar Datasets
Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
2018-08-06 | GSE111179 | GEO
Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
2018-08-06 | GSE111178 | GEO
Project description:NPM1-mutated acute myeloid leukemia (AML) accounts for one third of AML in adults. NPM1-mutated AML maintenance depends on the interaction between mutated NPM1 (NPM1c) and the nuclear exporter Exportin 1 (XPO1). In this work, we show that continous XPO1 inhibition is necessary to achieve stable disruption of the NPM1c-XPO1 interaction and to induce HOX downregulation and differentiation of AML cells with mutated NPM1. In contrast, intermittent XPO1 inhibition only results in minimal transcriptional perturbation and limited antileukemic activity.
2022-09-21 | GSE181176 | GEO
Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.
2024-08-14 | GSE274558 | GEO
Project description:Mutant NPM1 marginally impacts translation in AML cells
| PRJNA1055925 | ENA
Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.
2024-08-14 | GSE274559 | GEO
Project description:The nucleolar scaffold protein NPM1 acts as a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants that promote its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. In order to identify the proteome changes upon NPM1 and NPM1c overexpression, we performed TMT-labeled mass spectrometry analysis of whole cell lysates.
2023-11-20 | PXD040193 | Pride
Project description:C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event that reprograms leukemic-associated transcription program to transform hematopoietic stem and progenitor cells (HS/PCs). However, molecular mechanism underlying NPM1C+-driven leukemogenesis remain elusive. Here, we reported that NPM1C+ reprograms MIZ-1/MYC regulatory axis by altering NPM1-associated CTCF-driven topologically associated domains (TADs) that switched the balance of MIZ1 interaction with co-repressors MYC/G9A and coactivator p300 to control cell cycle progress and myeloid lineage-specific PU.1/CEBPa transcription networks. These alterations impaired hematopoietic cell cycle progression and myeloid differentiation. Knock-in of NPM1C+ in bone marrow HSPCs alters cell cycle regulators and myeloid master transcription factor (TF) TAD topology, chromatin accessibility, and gene regulation leading blockage of myeloid differentiation. Retention of NPM1 or reactivation of PU.1 or CEBPa within nucleus activates differentiation program by reorganizing TADs critical for myeloid TFs and cell cycle regulator, leading to blockage of NPM1C+-driven leukemogenesis. Thus, our data revealed that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription program require for cell cycle progression and leukemic progression. Restoration of myeloid transcription program in nucleus reversed NPM1C+-driven transcription signature and promotes myeloid differentiation leading to mitigation of AML.
2023-08-09 | GSE208022 | GEO
Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
2022-02-27 | GSE197383 | GEO
Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
2022-02-27 | GSE197381 | GEO