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 HSCs1,2,3,4 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 HSCs5,6. 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+ MSCs5,6 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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We thank S. Martín-Salamanca, A. M. Martín, A. B. Ricote, J. M. Ligos, S. Bartlett and the CNIC Comparative Medicine, Genomics and Bioinformatics Units for assistance; members of S.M.-F. and B. Ibáñez groups and M. García-Fernández for data discussion; G. Enikolopov, G. Fishell and D. Riethmacher for providing mice. This work was supported by Fundación CNIC, Spanish Ministry of Economy and Competitiveness (TerCel, Spanish Cell Therapy Network; Plan Nacional SAF-2011-30308) and ConSEPOC-Comunidad de Madrid S2010/BMD-2542 grants to S.M.-F.; Ramón y Cajal Program grants RYC-2009-04703/2011-09726 and Marie Curie grants FP7-PEOPLE-2011-RG-294262/294096 to A.S.-A. and S.M.-F.; Swiss National Science Foundation 310000-120724/1, 32003BB_135712/1 and Swiss Cancer League KLS-02398-02-2009 grants to R.C.S.; A.S.-A. received a Research Fellowship from the European Hematology Association. S.M.-F. is supported in part by an International Early Career Scientist grant of the Howard Hughes Medical Institute.
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Diabetes/Metabolism Research and Reviews (2019)