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Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

Original publication

DOI

10.1016/j.stem.2017.11.006

Type

Journal article

Journal

Cell Stem Cell

Publication Date

04/01/2018

Volume

22

Pages

64 - 77.e6

Keywords

acute myeloid leukemia, blood vessels, bone marrow, endosteum, hematopoietic stem cells, intravital microscopy, microenvironment, osteoblasts, transendothelial migration, Animals, Bone Marrow, Cell Count, Hematopoiesis, Hematopoietic Stem Cells, Humans, Intravital Microscopy, Leukemia, Myeloid, Acute, Mice, Inbred C57BL, Spleen, Stem Cell Niche, Stromal Cells, Time Factors, Tumor Microenvironment