19 October 2016

A new study reports on the role of abnormal signalling in the bone marrow on the development of leukaemia.

Dr Marc Raaijmakers of the Erasmus MC Cancer Institute, Rotterdam, the Netherlands, and colleagues previously found that genetic mutations in 'mesenchymal stem cells' in the bone marrow can lead to malignant changes in hematopoietic stem cells. In tests on mice, this increased the risk of leukemia.

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So the team went on to examine the molecular mechanisms by which this tumour microenvironment contributes to the development of cancer.

They carried out RNA sequencing of mesenchymal cells in mice with the pre-leukemic disorder Shwachman-Diamond syndrome, and also of bone marrow samples from patients with a range of pre-leukaemic syndromes.

This showed that mesenchymal cells in disorders such as myelodysplastic syndrome are "under stress", the team reports, triggering the release of inflammatory molecules called S100A8 and S100A9, which in turn lead to mitochondrial and DNA damage in haematopoietic stem and progenitor cells.

In Cell Stem Cell on 22 September, they add: "Activation of this inflammatory pathway in mesenchymal cells predicted the development of leukaemia and clinical outcomes in human patients."

Dr Raaijmakers said: "This discovery sheds new light on the longstanding association between inflammation and cancer. The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukaemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukaemia."

He added that, if the findings are confirmed, "These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression."

Zambetti, N. A. et al. Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell 22 September 2016 doi: 10.1016/j.stem.2016.08.021

 

 

 

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