This study investigates the impact of *Dicer1* deletion in mesenchymal osteoprogenitors on hematopoiesis and the development of myelodysplasia and secondary leukemia. Key findings include: 1. **Impaired Osteoblastic Differentiation**: *Dicer1* deletion in osteoprogenitors leads to reduced osteogenic differentiation, as evidenced by decreased colony-forming ability, reduced alkaline phosphatase activity, and altered bone matrix deposition. 2. **Myelodysplasia in OCD^fl/fl^ Mice**: These mice exhibit leukopenia, anemia, thrombocytopenia, and dysplastic features in blood cells and bone marrow, recapitulating human myelodysplastic syndrome (MDS) characteristics. 3. **Environmental Induction of Myelodysplasia**: Transplantation experiments show that the hematopoietic phenotype in OCD^fl/fl^ mice is environmentally induced, as wild-type hematopoietic cells do not cause the observed phenotype in mutant recipients, and vice versa. 4. **Osteolineage Stage Specificity**: Co-culture experiments with stromal cells from OCD^fl/fl^ mice reveal increased proliferation and impaired differentiation of hematopoietic cells, indicating a direct effect of osteoprogenitor cells on hematopoiesis. 5. **Emergence of Leukemia**: Sporadic myeloid sarcomas and acute myelogenous leukemia (AML) were observed in OCD^fl/fl^ mice, with genetic changes facilitating tumor evolution. 6. **Deletion of Shwachman-Diamond-Bodian Syndrome Gene**: Conditional deletion of *Sbds* in osteoprogenitors recapitulates many features of OCD^fl/fl^ mice, suggesting a role in the pathogenesis of Shwachman-Diamond syndrome. These findings highlight the critical role of specific mesenchymal cells in regulating hematopoiesis and the potential for microenvironmental factors to initiate and promote hematological disorders.This study investigates the impact of *Dicer1* deletion in mesenchymal osteoprogenitors on hematopoiesis and the development of myelodysplasia and secondary leukemia. Key findings include: 1. **Impaired Osteoblastic Differentiation**: *Dicer1* deletion in osteoprogenitors leads to reduced osteogenic differentiation, as evidenced by decreased colony-forming ability, reduced alkaline phosphatase activity, and altered bone matrix deposition. 2. **Myelodysplasia in OCD^fl/fl^ Mice**: These mice exhibit leukopenia, anemia, thrombocytopenia, and dysplastic features in blood cells and bone marrow, recapitulating human myelodysplastic syndrome (MDS) characteristics. 3. **Environmental Induction of Myelodysplasia**: Transplantation experiments show that the hematopoietic phenotype in OCD^fl/fl^ mice is environmentally induced, as wild-type hematopoietic cells do not cause the observed phenotype in mutant recipients, and vice versa. 4. **Osteolineage Stage Specificity**: Co-culture experiments with stromal cells from OCD^fl/fl^ mice reveal increased proliferation and impaired differentiation of hematopoietic cells, indicating a direct effect of osteoprogenitor cells on hematopoiesis. 5. **Emergence of Leukemia**: Sporadic myeloid sarcomas and acute myelogenous leukemia (AML) were observed in OCD^fl/fl^ mice, with genetic changes facilitating tumor evolution. 6. **Deletion of Shwachman-Diamond-Bodian Syndrome Gene**: Conditional deletion of *Sbds* in osteoprogenitors recapitulates many features of OCD^fl/fl^ mice, suggesting a role in the pathogenesis of Shwachman-Diamond syndrome. These findings highlight the critical role of specific mesenchymal cells in regulating hematopoiesis and the potential for microenvironmental factors to initiate and promote hematological disorders.