Letter | Published:

Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms

Nature volume 512, pages 7881 (07 August 2014) | Download Citation

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 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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Gene Expression Omnibus

Data deposits

The gene expression data have been deposited in the Gene Expression Omnibus (GEO) databank (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE55802.

References

  1. 1.

    et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005)

  2. 2.

    et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005)

  3. 3.

    et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387–397 (2005)

  4. 4.

    et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061 (2005)

  5. 5.

    et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010)

  6. 6.

    , , & Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008)

  7. 7.

    et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010)

  8. 8.

    et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 129, 1097–1110 (2007)

  9. 9.

    , , , & Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129, 1081–1095 (2007)

  10. 10.

    et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008)

  11. 11.

    et al. Neovascular niche for human myeloma cells in immunodeficient mouse bone. PLoS ONE 7, e30557 (2012)

  12. 12.

    et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 3, e270 (2006)

  13. 13.

    et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108, 3472–3476 (2006)

  14. 14.

    et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 369, 2379–2390 (2013)

  15. 15.

    et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 369, 2391–2405 (2013)

  16. 16.

    , , & The role of mutations in epigenetic regulators in myeloid malignancies. Nature Rev. Cancer 12, 599–612 (2012)

  17. 17.

    et al. Mutations and prognosis in primary myelofibrosis. Leukemia 27, 1861–1869 (2013)

  18. 18.

    et al. Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion. Cell Rep. 3, 1714–1724 (2013)

  19. 19.

    et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111, 3931–3940 (2008)

  20. 20.

    et al. Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Blood 121, 1188–1199 (2013)

  21. 21.

    et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285–299 (2013)

  22. 22.

    et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011)

  23. 23.

    et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996)

  24. 24.

    et al. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 117, 429–439 (2011)

  25. 25.

    , , & Monocyte adhesion in patients with bone marrow fibrosis is required for the production of fibrogenic cytokines. Potential role for interleukin-1 and TGF-beta. J. Immunol. 153, 2819–2830 (1994)

  26. 26.

    et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nature Med. 19, 695–703 (2013)

  27. 27.

    , , , & Neural stem and progenitor cells in nestin-GFP transgenic mice. J. Comp. Neurol. 469, 311–324 (2004)

  28. 28.

    & Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J. Neurosci. 27, 14248–14259 (2007)

  29. 29.

    , , , & Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb. Cortex 19 (Suppl. 1). i1–i10 (2009)

  30. 30.

    , , & An improved mouse line for Cre-induced cell ablation due to diphtheria toxin A, expressed from the Rosa26 locus. Genesis 44, 322–327 (2006)

  31. 31.

    , , , & Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc. Natl Acad. Sci. USA 95, 14423–14428 (1998)

  32. 32.

    & Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 71, 973–985 (1992)

  33. 33.

    et al. Production of chick embryo extract for the cultivation of murine neural crest stem cells. J. Vis. Exp. 45, e2380 (2010)

  34. 34.

    , , & Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nature Protocols 1, 2803–2812 (2007)

  35. 35.

    & GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 23, 1846–1847 (2007)

  36. 36.

    , & Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007)

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Acknowledgements

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.

Author information

Affiliations

  1. Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain

    • Lorena Arranz
    • , Abel Sánchez-Aguilera
    • , Daniel Martín-Pérez
    • , Joan Isern
    • , Xavier Langa
    •  & Simón Méndez-Ferrer
  2. University Hospital Basel, CH-4031 Basel, Switzerland

    • Alexandar Tzankov
    • , Pontus Lundberg
    • , Jürg Schwaller
    •  & Radek C. Skoda
  3. Department of Haematology, IBSAL-Hospital Universitario de Salamanca, 37007 Salamanca, Spain

    • Sandra Muntión
  4. National Taiwan University, Taipei 10002, Taiwan

    • Yi-Shiuan Tzeng
    •  & Dar-Ming Lai

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Contributions

L.A. designed and performed most experiments and analyses, prepared figures and wrote the manuscript. A.S.-A. performed in vivo transplantation assays. D.M.-P. performed qPCR, genome-wide expression analyses and together with X.L. provided technical assistance. J.I. performed neonatal cell isolation and culture. X.L. and A.T. performed histological analyses. S.M. provided human samples. Y.-S.T. and D.-M.L. provided Cxcl12-floxed mice. P.L., J.S. and R.C.S. provided samples, designed experiments and human studies. S.M.-F. designed the overall study, supervised the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Simón Méndez-Ferrer.

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DOI

https://doi.org/10.1038/nature13383

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