Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML

Summary

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.

Graphical Abstract

Highlights

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  AML leads to progressive remodeling of endosteal stroma

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  HSC loss is spatiotemporally correlated with endosteal remodeling

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  In vivo imaging reveals transendothelial migration of healthy hematopoietic cells

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  Rescue of endosteal vessels preserves HSCs and enhances the efficacy of chemotherapy

Abstract

Multi-modal microscopy of acute myeloid leukemia progression within the bone marrow reveals focal and progressive remodeling of endosteal blood vessels coupled to loss of osteoblasts, hematopoietic stem cells (HSCs), and HSC niches. Preserving endosteal vessels increases the number of surviving HSCs and improves the efficacy of chemotherapy.