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Series GSE55798 Query DataSets for GSE55798
Status Public on Mar 12, 2014
Title Neuropathy of the haematopoietic stem cell niche is essential for myeloproliferative neoplasms [RNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.
Overall design CD45- CD31- Ter119- GFP+ cells were sorted from the BM of Nes-gfp;Mx1-cre;JAK2-V617F mice and control littermates 6 weeks after pIpC treatment and were subjected to RNA sequencing. Each sample was pooled from 3 animals of the same genotype.
Contributor(s) Arranz L, Mendez-Ferrer S
Citation(s) 25043017
Submission date Mar 11, 2014
Last update date May 15, 2019
Contact name Simón Méndez-Ferrer
Organization name CNIC
Lab Stem cell niche pathophysiology
Street address Calle Melchor Fernández Almagro, 3
City Madrid
ZIP/Postal code 28029
Country Spain
Platforms (1)
GPL11002 Illumina Genome Analyzer IIx (Mus musculus)
Samples (2)
GSM1346215 Control littermates (n=3)
GSM1346216 Mx1cre-JAK2V617F 6wks post-induction (n=3)
This SubSeries is part of SuperSeries:
GSE55802 Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms
BioProject PRJNA241021
SRA SRP039968

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Supplementary file Size Download File type/resource
GSE55798_CvsMx_FPKMs.txt.gz 723.8 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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