Mesenchymal cell populations contribute to microenvironments regulating stem cells and the
growth of malignant cells. Osteolineage cells participate in the hematopoietic stem cell niche.
Here, we report that deletion of the miRNA processing endonuclease Dicer1 selectively in
mesenchymal osteoprogenitors induces markedly disordered hematopoiesis. Hematopoietic
changes affected multiple lineages recapitulating key features of human myelodysplastic
syndrome (MDS) including the development of acute myelogenous leukemia. These changes were
microenvironment dependent and induced by specific cells in the osteolineage. Dicer1−/−
osteoprogenitors expressed reduced levels of Sbds, the gene mutated in the human bone marrow
failure and leukemia predisposition Shwachman-Bodian-Diamond Syndrome. Deletion of Sbds in
osteoprogenitors largely phenocopied Dicer1 deletion. These data demonstrate that differentiation
stage-specific perturbations in osteolineage cells can induce complex hematological disorders and
indicate the central role individual cellular elements of ‘estroma’ can play in tissue homeostasis.
They reveal that primary changes in the hematopoietic microenvironment can initiate secondary
neoplastic disease.