Acute myeloid leukemia associated alteration of the bone marrow microenvironment
Recent studies have suggested that the initiation and progression of leukemias also depend on their ability to interact with the non-malignant microenvironment, which produces fundamental factors for leukemic cell survival and at the same time adapts to their own needs to promote the progression. This represents an almost unexplored field of study in acute myeloid leukemia (AML), which could provide a more complete picture of initiation, progression and drug resistance mechanisms, and help identify new potential therapeutic targets. We are studying the leukemic microenvironment in the bone marrow of immunodeficient mice engrafted with patient-derived AML samples by using intravital multiphoton imaging and RNA sequencing techniques. We have identified several abnormalities in vascular architecture and function. In particular increased vascular permeability, a chemotherapy resistant phenotype, is associated with an increase in nitric oxide (NO) levels produced by endothelial cells in the bone marrow. Treatment of mice with NO inhibitors restores vascular functionality, promoting higher efficiency of chemotherapy and normalization of the vascular niche for hematopoietic stem cells. Recently, we bioengineered 3D organoids in mice to model the human BM microenvironment. These humanized tissues constitute a valuable in vivo platform we are currently using to translate our observations to the human normal and malignant BM niche.
Haematopoietic Stem Cell Laboratory,The Francis Crick Institute
Domain 1 - UMR 3348 - Genotoxic Stress and Cancer