Niche Induced Myelodysplasia and Secondary Hematopoietic Neoplasia Caused by Deletion of Dicer1 in Osteoprogenitor Cells.

Mesenchymal cells are a part of virtually every tissue in metazoans and are thought to participate in organ formation and homeostasis. In the hematopoietic system, mesenchymal cells of the osteoblast lineage have revealed their role as regulators of normal stem cell and hematopoietic physiology. Whether these cells, which have been relegated a relatively non-descript role of ‘stroma', participate in processes that result in disease is relatively understudied.

To explore this, we conditionally deleted Dicer1, the endonuclease essential for miRNA biogenesis, from osteoprogenitor cells by intercrossing transgenic mice expressing a GFP-Cre recombinase under the transcriptional control of the osteoblastic lineage specific osterix promoter to mice containing conditional (floxed) Dicer1 alleles.

Deletion of Dicer1 from osteoprogenitor cells resulted in markedly disordered hematopoiesis, affecting multiple lineages and recapitulating key features of human myelodysplastic syndrome (MDS). These features included ineffective hematopoiesis with cytopenia, multilineage dysplasia, increased proliferation and intramedullary apoptosis of primitive hematopoietic cells, decreased B-cell progenitors, increased bone marrow vascularity and the propensity to develop hematopoietic neoplasms (myeloid sarcoma and acute monocytic leukemia-like disease). Comparative genomic hybridization of tumor and germline tissues revealed multiple genetic aberrancies in myeloid sarcomas induced by the Dicer1 deleted environment. The hematopoietic abnormalities were entirely microenvironment dependent with intact Dicer1 in hematopoietic cells. Transplantation of wild-type hematopoietic cells into the mutant environment recapitulated these abnormalities whereas, conversely, transplantation of hematopoietic cells from mutant mice into a wild-type environment resulted in complete normalization of hematopoiesis. In addition, hematopoietic abnormalities were not observed when Dicer1 was deleted from mature osteoblasts indicating a central role of osteoprogenitor cells in the regulation of hematopoiesis. Finally, gene expression profiling and cytokine arrays from osteoprogenitor cells identified candidate molecular effectors of the observed hematopoietic abnormalities.

The data demonstrate that a distinctive, differentiation stage specific, stromal subset of osteolineage cells can induce a highly dysfunctional hematopoietic system, recapitulating key characteristics of human myelodysplastic syndrome. Further, they reveal that primary changes in a tissue microenvironment can initiate neoplastic disease.

Scadden:Fate Therapeutics: Consultancy.