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Nature. 2014 Aug 7;512(7512):78-81. doi: 10.1038/nature13383. Epub 2014 Jun 22.

Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.

Author information

1
Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
2
University Hospital Basel, CH-4031 Basel, Switzerland.
3
Department of Haematology, IBSAL-Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
4
National Taiwan University, Taipei 10002, Taiwan.

Abstract

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 microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow 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 bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1β produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with β3-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of 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.

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PMID:
25043017
DOI:
10.1038/nature13383
[Indexed for MEDLINE]
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