Mesenchymal cells contribute to the ‘stroma’ of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman–Bodian–Diamond syndrome—a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.
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We thank E. Schipani, E. Attar and H. Kronenberg for advice and discussion, A. McMahon for providing the Osx-Cre mice, J. Fujisaki, D. Wilpitz, M. Ohishi, S. Vallet, M. Churchill and G. Frankl for technical assistance, the Histocore (Endocrine Unit), Flow Core at the Center for Regenerative Medicine, Massachusetts General Hospital (L. Pickett and K. Folz-Donahue), and F. Preffer and D. Dombrowski for assistance with histology and flow-cytometry. We thank D. Machon for help preparing the manuscript and the Cytogenetics Core at Brigham Women/Dana Farber (Y. Xiao and C. Lee) for performing CGH analyses. This work was supported by a Fellowship Award of the Dutch Cancer Society (KWF) and a Special Fellowship Award of The Leukemia & Lymphoma Society to M.H.G.P.R. and grants of the National Institutes of Health, the Harvard Stem Cell Institute and the Ellison Medical Foundation to D.T.S.
Author Contributions M.H.G.P.R., S.G. and D.T.S. initiated the study. M.H.G.P.R., S.M. and D.T.S. designed the experiments and analysed the data. M.H.G.P.R. carried out most of the experimental work with the help of S.M., J.A.S., T.K., S.G., E.O.S., S.Z., M.M. and Z.A. B.L.E. and F.A.-S. analysed the microarray results. R.P.H. reviewed bone marrow histology and peripheral blood morphology. C.L. supervised the in vivo imaging studies. M.M. and J.M.R. provided materials and discussion. M.H.G.P.R. and D.T.S. wrote the manuscript. D.T.S. directed the research. All authors discussed and commented on the manuscript.
This file contains Supplementary Figures 1-18 with legends, Supplementary Tables 1-3, Supplementary Methods and Materials and Supplementary References.
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Nature Reviews Immunology (2019)