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The Pediatric Leukemia Oncoprotein NUP98-KDM5A Induces Genomic Instability That May Facilitate Malignant Transformation

ABSTRACT: The Pediatric Leukemia Oncoprotein NUP98-KDM5A Induces Genomic Instability That May Facilitate Malignant Transformation

PROVIDER: PRJNA931337 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23335543_1.fastq.gz	Fastqsanger.gz
	SRR23335543_2.fastq.gz	Fastqsanger.gz
	SRR23335544_1.fastq.gz	Fastqsanger.gz
	SRR23335544_2.fastq.gz	Fastqsanger.gz
	SRR23335545_1.fastq.gz	Fastqsanger.gz

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The Pediatric Leukemia Oncoprotein NUP98-KDM5A Induces Genomic Instability That May Facilitate Malignant Transformation

Project description:Pediatric Acute Myeloid Leukemia (AML) is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations. Despite the improvement of survival in the last years, about 50% of patients still experience a relapse. It is not possible to improve prognosis only with further intensification of chemotherapy, as come with a severe cost to the health of patients, often resulting in treatment-related death or long-term sequels. To design more effective and less toxic therapies we need a better understanding of pediatric AML biology. The NUP98-KDM5A chimeric protein is exclusively found in a particular subgroup of young pediatric AML patients with complex karyotypes and poor prognosis. In this study, we investigated the impact of NUP98-KDM5A expression on cellular processes in human Pluripotent Stem Cell models and the CHRF-288-11 cell line. We found that NUP98-KDM5A generates genomic instability through two complementary mechanisms that involve accumulation of DNA damage and direct interference of RAE1 activity during mitosis. Overall, our data support that NUP98-KDM5A promotes genomic instability and likely contributes to malignant transformation.

2023-05-02 | GSE224499 | GEO

The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation.

Project description:Pediatric Acute Myeloid Leukemia (AML) is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations. Despite the improvement of survival in the last years, about 50% of patients still experience a relapse. It is not possible to improve prognosis only with further intensification of chemotherapy, as come with a severe cost to the health of patients, often resulting in treatment-related death or long-term sequels. To design more effective and less toxic therapies we need a better understanding of pediatric AML biology. The NUP98-KDM5A chimeric protein is exclusively found in a particular subgroup of young pediatric AML patients with complex karyotypes and poor prognosis. In this study, we investigated the impact of NUP98-KDM5A expression on cellular processes in human Pluripotent Stem Cell models and a patient-derived cell line. We found that NUP98-KDM5A generates genomic instability through two complementary mechanisms that involve accumulation of DNA damage and direct interference of RAE1 activity during mitosis. Overall, our data support that NUP98-KDM5A promotes genomic instability and likely contributes to malignant transformation.

| S-EPMC10257648 | biostudies-literature

Human models of NUP98-KDM5A megakaryocytic leukemia contribute to uncover new biomarkers and therapeutic vulnerabilities

Project description:We generated human synthetic models of NUP98-KDM5A leukemia and compared gene expression profiles to primary pediatric samples.

2019-11-25 | GSE123485 | GEO

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Project description:The dysregulation of plant homeodomain (PHD) fingers has been implicated in several human diseases, including cancer. In a subset of aggressive acute myeloid leukemia (AML), chromosomal translocations that involve nucleoporin 98 (NUP98), a component of the nuclear pore complex, and a PHD finger-containing protein, such as KDM5A/JARID1A, PHF23 and BPTF, generate potent oncoproteins (namely NUP98-KDM5A, NUP98-PHF23 and NUP98-BPTF; or together termed as NUP98-PHD fusions) that are able to arrest hematopoietic differentiation and induce acute myeloid leukemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukemic transformation. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98-PHD finger fusions. Disulfiram (DS), a small molecule compound that directly targets the PHD finger, shows anti-proliferation effects in AML cells expressing NUP98-PHD through the conserved inhibitory mechanism. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.

2020-07-13 | GSE146693 | GEO

NUP98-HOXA9 acute myeloid leukemia

Project description:Mass Spectrometry analysis of the interactome of the oncoprotein NUP98-HOXA9

2017-07-10 | PXD001828 | Pride

Nuclear Condensation of NUP98-Fusion Proteins drives leukemogenic gene expression

Project description:NUP98-fusion proteins cause acute myeloid 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, different C-terminal NUP98-fusion partners are often transcriptional and epigenetic regulators. 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 of five distinct NUP98-fusion proteins revealed a conserved set of interactors that was highly enriched for proteins involved in biomolecular condensation. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. In addition, an artificial FG-repeat containing fusion protein was able to phenocopy the induction of leukemic gene expression as mediated by NUP98-KDM5A. Thus, we propose that IDR-containing fusion proteins have evolved to uniquely combine biomolecular condensation with gene control to induce cancer.

2021-02-16 | GSE159037 | GEO

The oncoprotein NUP98-HOXD13 (NHD13) induces thymocyte self-renewal via Lmo2/Lyl1

Project description:The oncoprotein NUP98-HOXD13 (NHD13) induces thymocyte self-renewal via Lmo2/Lyl1

| PRJNA497916 | ENA

Gene expression profiles of KDM5A-/- MEFs with wild-type KDM5A or KDM5A-H483A mutant

Project description:Gene expression profiles of Immortalized KDM5A-/- MEFs with re-introduction of wild-type KDM5A or KDM5A-H483A mutant.

2017-02-08 | GSE84309 | GEO

Phase Separation by the NUP98-HOXA9 Fusion Oncoprotein Drives an Oncogenic Phenotype in Hematopoietic Cells

Project description:RNA-seq of mouse hematopoietic stem and progenitor cells expressing NUP98-HOXA9 (NHX9) show upregulation of HOX and other NUP98 fusion target genes, but expression changes are dampened or lost with the introduction of mutations in NUP98's FG repeats or HOXA9's DNA binding domain

2021-10-13 | GSE185621 | GEO

Human models of NUP98-KDM5A megakaryocytic leukemia contribute to uncover new biomarkers and therapeutic vulnerabilities

Project description:Human models of NUP98-KDM5A megakaryocytic leukemia contribute to uncover new biomarkers and therapeutic vulnerabilities

| PRJNA508928 | ENA