Bone Progenitor Dysfunction Induces Myelodysplasia and Secondary Leukaemia

Nature. 2010 Apr 8;464(7290):852-7. doi: 10.1038/nature08851. Epub 2010 Mar 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Cell Differentiation
  • Cell Lineage
  • Female
  • Gene Deletion
  • Hematopoiesis / genetics
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Mesoderm / cytology
  • Mice
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology*
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Phenotype
  • Proteins / genetics
  • Proteins / metabolism
  • Ribonuclease III / deficiency
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Sarcoma, Myeloid / genetics
  • Sarcoma, Myeloid / metabolism
  • Sarcoma, Myeloid / pathology
  • Stem Cell Niche / metabolism
  • Stem Cell Niche / pathology
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology

Substances

  • Proteins
  • Sbds protein, mouse
  • Ribonuclease III