How to say NO to vascular disruption and stem cell mobilization

摘要

Acute myeloid leukemia (AML) is an aggressive cancer affecting mostly adult and elderly patients. The common clinical practice remains unchanged since decades, consisting of sequential courses of standard chemotherapy. As a result of this non-specific treatment, resistance and relapse frequently occur after treatment. Transplantation of donor-derived healthy stem cells represents another major line of intervention, aimed to replenish the bone marrow (BM) with normal hematopoietic cells. However, recent preclinical findings have evidenced a severe vascular pathology occurring in the BM of AML xenog rafts, causing vascular leakiness and mobilization of healthy stem cells to the periphery, chasing them away from their protective niche environment and therefore exposing them to drug toxicity. This vascular dysfunction could represent a severe obstacle to the success of the stem cell transplantation approach, limiting the out-competition effect of both patient residual and donor-derived stem cell on the leukemic clones (graft versus leukemia). Thus, finding a strategy to keep healthy stem cells in the BM could significantly improve treatment outcome. Hence, recent literature addressing the molecular mechanisms of stem cell anchorage to the niche highlighted nitric oxide (NO) as a potential valuable target. The choice of the best therapeutic strategy would require further characterization of the mechanisms regulating NO production in the BM microenvironment. Yet, the most challenging step would be to move these studies from the bench to the bedside for a clinical assessment of their efficacy in combination with standard chemotherapy.