Depletion of Jak2V617F MPN-propagating stem cells by interferon-alpha in a murine model of polycythemia vera
Transcriptomics Dataset
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General Information
AccessionGSE44961
TitleDepletion of Jak2V617F MPN-propagating stem cells by interferon-alpha in a murine model of polycythemia vera
DescriptionInterferon alpha (IFNa) is an effective treatment for patients with myeloproliferative neoplasms (MPN). In addition to inducing hematological responses in most MPN patients, IFNa reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNa on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNa on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNa treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNa treatment induces cell-cycle activation of Jak2V617F mutant long-term hematopoietic stem cells (LT-HSC) and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNa on Jak2V617F mutant and normal hematopoiesis and suggest that IFNa achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN, by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNa and targeting the proliferating downstream progeny with JAK2-inhibitors or cytotoxic chemotherapy.
Landing Pagehttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44961
RepositoryGene Expression Omnibus
Tools used to analyze the dataset
Keyword
Dataset Accession
Enrichr
Published May 2016
A comprehensive gene set enrichment analysis web server 2016 update
7759
65
Characteristic Direction
Published March 2014
A geometrical multivariate approach to identify differentially expressed genes
26829
GeneMANIA
Published June 2010
Biological network integration for gene prioritization and predicting gene function
7435
L1000CDS2
Published August 2016
An ultra-fast LINCS L1000 Characteristic Direction signature search engine
7756
PAEA
Published November 2015
Enrichment analysis tool implementing the principal angle method
3879
Canned Analyses generated with the dataset
Filters  
Dataset Accession
Tool Name
Direction
Geneset
Small molecules which mimic JAK2 activemutant
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse JAK2 activemutant
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Enrichment analysis of genes dysregulated in JAK2 activemutant
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Interaction network and enrichment analysis of genes downregulated in JAK2 activemutant
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Interaction network and enrichment analysis of genes upregulated in JAK2 activemutant
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Enrichment analysis of genes downregulated in JAK2 activemutant
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most downregulated genes identified by...
Enrichment analysis of genes upregulated in JAK2 activemutant
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most upregulated genes identified by a...
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