Evidence for Niche-Induced Oncogenesis
Schwachman-Bodian-Diamond syndrome is a precondition for leukaemia. Characterised by bone marrow dysfunction, the underlying causes of the syndrome, first documented in the 1960s, are still not well understood.
Now, CSC collaborator David Scadden and his team at Massachussetts General Hospital and Harvard Medical School, in collaboration with Matthias Merkenschlager (CSC Lymphocyte Development), have reported findings that may go some way to uncovering the abnormal developmental mechanisms that lead to the syndrome. They crossed mice lacking the gene Dicer – which is important in the biogenesis of microRNAs – with another strain expressing a tagged protein under the transcriptional control of of a promoter (‘osterix’) found in osteoblasts. Osteoblasts in bone marrow provide the tissue-specific niches for haematopoietic stem cells, which are the progenitors of all the cells constituent in blood. The mouse strain resulting from the cross-breeding carried out in the study was deficient in Dicer specifically in osteoblast progenitors and their progeny, including osteoblast precursors and mature osteoblasts. While the specificity of the osterix promoter was such that Dicer was expressed normally in haematopoietic stem cell, bone marrow dysfunction – or myelodysplasia – was observed in addition to a reduction in white blood cells. Some of the mice eventually developed secondary leukaemias.
This phenotype is highly reminiscent Shwachman-Bodian-Diamond syndrome. Deletion of the gene mutated in the syndrome Sbds in osteoprogenitor cells recreated the haematopoietic phenotype in the Dicer-deficient mice.
Although precisely which microRNAs in osteoblasts are crucial for haematopoiesis requires further investigation, the study has demonstrated that abnormalities in stromal cells such as osteoblasts can result in tumourigenesis in other cells.
Raaijmakers, M. H. G. P., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J. A., Ebert, B. L., Al-Shahrour, F., Hasserjian, R. P., Scadden, E. O., Aung, Z., Matza, M., Merkenschlager, M., Lin, C., Rommens, J. M., Scadden, D., March 2010. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464 (7290), 852-857.