Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Acute Myeloid Leukemia Progression and Drug Response

The biological and clinical behavior of hematological malignancies are not only determined by the properties of the leukemic cells themselves, but are also highly affected by interaction with the microenvironment, pointing to the existence of an active crosstalk between the two compartments. Previous studies showed that acute myeloid leukemia (AML) cells actively modify endothelial cells ex vivovia several pathways, mainly mediated by VEGF. However, as anti-VEGF therapies haven't produced successful results in clinical trials, an extensive study of the crosstalk between AML and the vascular niche in the bone marrow (BM) is required to provide new therapeutic strategies. In the present study we combined the use of mouse models of AML, human AML patient-derived xenografts (PDX) and direct analysis on patient-derived BM biopsies to provide a global, reliable picture of the bone marrow vasculature in AML disease. We found several abnormalities in the vascular architecture and function in PDX, such as increased number of endothelial cells, increased microvascular density (MVD), decreased vascular mean diameter and increased hypoxia. Furthermore, using two-photon confocal intravital imaging we witnessed increased vascular permeability upon AML engraftment, observed homogeneously among different PDX. Interestingly, induction chemotherapy failed to normalize the vascular permeability in the BM, despite significant reduction in AML engraftment. We identified increased nitric oxide (NO) as a major mediator of the AML-induced vascular leakiness in the BM. Increased levels of NO and activated NOS3 were found in PDX and in an independent cohort of patient-derived BM biopsies. Strikingly, inhibition of NO production using genetic and pharmacological approaches reduced the vascular permeability, potentiated the normal HSC function and significantly improved treatment response in PDX. These results strongly support the notion of a primary function of the vascular permeability in AML progression, drug response and in affecting normal stem cell function, and they call for clinical trials incorporating NOS inhibitors during the remission phase to target the abnormal vascular niche and improve the treatment response.