stem cells

Dominique Bonnet : Leukaemia cells impede their vascular niche

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Vascular leakiness in the bone marrow of patient derived xenografts.

Figure 1: Vascular leakiness in the bone marrow of patient derived xenografts.

In leukaemia, the hematopoietic stem cell (HSC) niche has recently emerged as an oncogenic unit. Leukaemic cells can indeed turn bone marrow niches into “leukaemic niches”, which support them and impairs the maintenance of normal HSC. We show the direct impact of leukaemic cells on the vascular niche and demonstrate the therapeutic potential of inhibiting nitric oxide production in combination to conventional chemotherapy to eradicate acute myeloid leukaemia.

Using invasive intra-vital imaging technique, we show perturbation of the vasculature in presence of leukaemia and provided a detailed picture of the BM vasculature in acute myeloid leukaemia. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia.

Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX (see D Passaro et al., Cancer Cell, 2017).