Cytoplasmic NPM1 maintains the leukemic state through HOX expression [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA436124 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6786730.fastq.gz | Fastqsanger.gz | |||
| SRR6786740.fastq.gz | Fastqsanger.gz | |||
| SRR6786731.fastq.gz | Fastqsanger.gz | |||
| SRR6786741.fastq.gz | Fastqsanger.gz | |||
| SRR6786732.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
Similar Datasets
Project description:Cytoplasmic NPM1 maintains the leukemic state through HOX expression
| PRJNA436120 | ENA
Project description:Cytoplasmic NPM1 maintains the leukemic state through HOX expression [RNA-seq]
| PRJNA436127 | ENA
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 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); 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 immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated 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.
| S-EPMC6159911 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-08-06 | GSE111180 | 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: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:Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML in vitro and in vivo. Combined pharmacological inhibition of menin-MLL and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Together, MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1 and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on target activity and constitutes a novel therapeutic concept for this common AML subtype. RNA sequencing data of the human AML cell lines OCI-AML2 and OCI-AML3 comparing EPZ004777 [10µM] drug treatment versus DMSO vehicle control; experiments performed in biological triplicates.
2016-08-22 | E-GEOD-85107 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
2008-03-14 | E-TABM-429 | biostudies-arrayexpress