These studies show that specific changes in specific mesenchymal cells of the hematopoietic microenvironment may be sufficient to initiate a complex phenotype of disordered homeostasis with similarities to myelodysplasia, a poorly understood human disease. Further, we demonstrate the ability of this abnormality to result in the emergence of a clonal neoplasm in a cell type of clearly distinct lineage with distinct secondary genetic changes. The data indicate that individual, well defined, mesenchymal microenvironment constituents can be primary enablers of neoplastic changes in a heterologous cell type.
While a series of genetic and epigenetic events in a single cell may be necessary for oncogenesis, they may not be sufficient and a permissive microenvironment has been hypothesized to be required for frank malignancy to emerge26
. Examples of microenvironmental contributions to neoplasia include a necessary mast cell contribution to Nf1 induced neurofibromas27
and mesenchymal cell alteration of epithelial tumor growth kinetics28,29
. Changes in a tissue microenvironment have also been suggested to precede and promote the initiation of genetic events by creating a “pre-malignant” state characterized by disruption of quiescence inducing signals or increases in proliferative signaling30,31
. This has been validated experimentally with altered TGF-β signaling in tissue fibroblasts32
and with myeloid progenitor expansion following RAR-γ deletion in bone marrow or Rb deficiency in hematopoietic and microenvironmental cells33,34
Our findings further the paradigm of malignancy resulting from the interplay of cell autonomous and microenvironmentally determined events and point to the microenvironment as the site of the initiating event that leads to secondary genetic changes in other cells. It is therefore possible to envision a ‘niche-based’ model of oncogenesis whereby a change in a specific microenvironmental cell can serve as the primary moment in a multi-step process toward malignancy of a supported, but distinct cell type. Signals from the microenvironment may select for subsequent transforming events and therefore such signals may represent candidate therapeutic targets in both treatment and prevention strategies.
Whether osteoprogenitor cell abnormalities play a role in the pathogenesis of human MDS and leukemia cannot be discerned from our studies. MDS is a heterogeneous disorder in which cytogenetics can be normal or reveal specific clonal lesions such as deletion of 5q. A role for the microenvironment in MDS has been raised, and reduced osteoblast surface and unchanged bone volume similar to our OCDfl/fl
model has been reported35
. Our findings raise the possibility that microenvironmental alterations may precede and facilitate clonal evolution in MDS. Studies examining patient samples will explore this possibility.
The Sbds studies provide further suggestive links to human disease. The human syndrome combines features seen in our model and raises the issue of whether both the pathophysiology of the disorder and the difficulty in treating this syndrome with bone marrow transplantation is in part due to a microenvironmental defect in the bone marrow.
The function of Sbds
is itself unclear, but it has been implicated in ribosomal biogenesis23
and may therefore share with Dicer1
the ability to modulate the gene expression ‘landscape.’ While we pursued Sbds
because its expression was decreased in the absence of Dicer1
, levels in OCSfl/fl
are likely to be even lower and as a consequence, may not faithfully portray the role of Sbds
in our model. We therefore regard Sbds
as a candidate participant in the phenotype of OCDfl/fl
mice, but further studies will be needed to define the collaborating molecules causing the hematopoietic abnormalities.
These studies were initiated focusing on the stem cell niche, but the results indicate that individual microenvironment constituents can serve as regulators of tissue functions beyond that of stem cell support. Osteoprogenitor dysfunction induced altered proliferation and differentiation of both HSCs and distinct hematopoietic progenitor subsets and induced changes in the tissue architecture. Within a tissue microenvironment, certain elements may have far broader, integrative functions as the osteoprogenitor cells did here. There may be a hierarchy of activity within niche components as well as the cells they regulate. Our studies provide the rationale for further exploration of the complexity of mesenchymal ‘stroma’ and the role specific mesenchymal subsets may play as primary regulators of normal and disordered tissue function.