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Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia

Nature volume 464, pages 852–857 (2010)Cite this article

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Abstract

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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Figure 1: Impaired osteoblastic differentiation in OCD fl/fl mice.
Figure 2: Myelodysplasia in OCD fl/fl mice.
Figure 3: Myelodysplasia in OCD fl/fl mice is induced by the bone marrow microenvironment.
Figure 4: Myeloid sarcoma and acute myelogenous leukaemia in OCD fl/fl mice.
Figure 5: Targeted deletion of the Sbds gene from osteoprogenitor cells recapitulates many features of the OCD fl/fl phenotype.

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Acknowledgements

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.

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Author notes

  1. Siddhartha Mukherjee

    Present address: Present address: Department of Medicine and Irving Cancer Research Center, Columbia University School of Medicine, New York 10032, USA.,

  2. Marc H. G. P. Raaijmakers and Siddhartha Mukherjee: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,,

    Marc H. G. P. Raaijmakers, Siddhartha Mukherjee, Shangqin Guo, Siyi Zhang, Jesse A. Schoonmaker, Edward O. Scadden, Zinmar Aung, Marc Matza & David. T. Scadden

  2. Cancer Center, Massachusetts General Hospital,,

    Siddhartha Mukherjee & David. T. Scadden

  3. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,,

    Tatsuya Kobayashi

  4. Department of Pathology, Massachusetts General Hospital and Harvard Medical School,

    Robert P. Hasserjian

  5. Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA ,

    Charles Lin

  6. Department of Stem Cell and Regenerative Biology, Harvard University,

    Marc H. G. P. Raaijmakers, Siddhartha Mukherjee, Shangqin Guo, Siyi Zhang, Jesse A. Schoonmaker, Edward O. Scadden, Zinmar Aung, Marc Matza & David. T. Scadden

  7. Harvard Stem Cell Institute,,

    Marc H. G. P. Raaijmakers, Siddhartha Mukherjee, Shangqin Guo, Siyi Zhang, Jesse A. Schoonmaker, Edward O. Scadden, Zinmar Aung, Marc Matza & David. T. Scadden

  8. Broad Institute, Cambridge, Massachusetts 02138, USA ,

    Benjamin L. Ebert & Fatima Al-Shahrour

  9. Hematology Division, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA,

    Benjamin L. Ebert & Fatima Al-Shahrour

  10. Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK ,

    Matthias Merkenschlager

  11. Department of Molecular Genetics, Program in Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    Johanna M. Rommens

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Correspondence to Marc H. G. P. Raaijmakers or David. T. Scadden.

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Raaijmakers, M., Mukherjee, S., Guo, S. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010). https://doi.org/10.1038/nature08851

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