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Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

ABSTRACT: Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

PROVIDER: PRJEB32989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3367520_1.fastq.gz	Fastqsanger.gz
	ERR3367520_2.fastq.gz	Fastqsanger.gz
	ERR3367530_1.fastq.gz	Fastqsanger.gz
	ERR3367530_2.fastq.gz	Fastqsanger.gz
	ERR3367540_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Mir142 loss unlocks IDH2<sup>R140</sup>-dependent leukemogenesis through antagonistic regulation of HOX genes.

Project description:AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

| S-EPMC7656267 | biostudies-literature

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

Project description:Acute myeloid leukaemia (AML) is genetically a genetically heterogeneous condition. It was observed that mutations in the micro RNA mir142 co-occurred with mutations in isocitrate dehdrogenase genes IDH1 and 2. These experiments intend to investigate the interaction between miR142 and IDH in AML.

2020-06-05 | E-MTAB-8042 | biostudies-arrayexpress

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

Project description:NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

| PRJNA1147210 | ENA

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation [Cut & Run]

Project description:NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation [Cut & Run]

| PRJNA1147212 | ENA

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

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

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation [Cut & Run]

2024-08-14 | GSE274559 | GEO

Homeodomain dependent gene expression in HOX transformed primary cells

Project description:The gene expression profile was determined in primary cells transformed by two different HOX genes (HOXA1 and HOXA9) and by two HOX derivatives where the homeodomain was exchanged.

2013-01-31 | E-MEXP-3617 | biostudies-arrayexpress

Antagonistic microorganisms

Project description:Antagonistic microorganisms - Whole Genome Sequencing

| PRJNA1170530 | ENA

Loss of Hoxa5 function affects Hox gene expression in different biological contexts

Project description:Loss of Hoxa5 function affects Hox gene expression in different biological contexts

| PRJNA1124161 | ENA

Loss of Hoxa5 function affects Hox gene expression in different biological contexts

Project description:Hoxa5 plays numerous roles in development, but its downstream molecular effects are mostly unknown. We applied bulk RNA_seq assays to characterize the transcriptional impact of the loss of Hoxa5 gene function in seven different biological contexts, including developing respiratory and musculoskeletal tissues that present phenotypes in Hoxa5 mouse mutants. This global analysis revealed few shared transcriptional changes, suggesting that HOXA5 acts mainly via the regulation of context_specific effectors. However, Hox genes themselves appeared as potentially conserved targets of HOXA5 across tissues. Notably, a trend toward reduced expression of HoxA genes was observed in Hoxa5 null mutants in several tissue contexts. Comparative analysis of epigenetic marks along the HoxA cluster in lung tissue from two different Hoxa5 mutant mouse lines revealed limited effect of either mutation indicating that Hoxa5 gene targeting did not significantly perturb the chromatin landscape of the surrounding HoxA cluster. Combined with the shared impact of the two Hoxa5 mutant alleles on phenotypes and Hox expression, these data argue against the contribution of local cis effects to Hoxa5 mutant phenotypes and support the notion that the HOXA5 protein acts in trans in the control of Hox gene expression.

2024-12-06 | GSE269950 | GEO

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