Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia

Marc H. G. P. Raaijmakers (), Siddhartha Mukherjee, Shangqin Guo, Siyi Zhang, Tatsuya Kobayashi, Jesse A. Schoonmaker, Benjamin L. Ebert, Fatima Al-Shahrour, Robert P. Hasserjian, Edward O. Scadden, Zinmar Aung, Marc Matza, Matthias Merkenschlager, Charles Lin, Johanna M. Rommens and David. T. Scadden ()
Additional contact information
Marc H. G. P. Raaijmakers: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Siddhartha Mukherjee: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Shangqin Guo: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Siyi Zhang: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Tatsuya Kobayashi: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,
Jesse A. Schoonmaker: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Benjamin L. Ebert: Broad Institute, Cambridge, Massachusetts 02138, USA
Fatima Al-Shahrour: Broad Institute, Cambridge, Massachusetts 02138, USA
Robert P. Hasserjian: Massachusetts General Hospital and Harvard Medical School
Edward O. Scadden: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Zinmar Aung: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Marc Matza: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,
Matthias Merkenschlager: Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK
Charles Lin: Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Johanna M. Rommens: Program in Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5S 1A8, Canada
David. T. Scadden: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, Room 4265A, 185 Cambridge Street,

Nature, 2010, vol. 464, issue 7290, 852-857

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature08851

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