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

Abstract

SummaryBone 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.

Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

“…However, there is still little information on the dynamics of AML cells themselves in vivo that support this hypothesis. We, and others, have reported AML to be associated with endosteal niches, but the dynamics of AML interactions with the BM microenvironment and whether this process is linked to AML chemoresistance and minimal residual disease remains unanswered. Using intravital microscopy, we recently showed that Notch1‐driven T‐cell acute lymphoblastic leukemia (T‐ALL) cells (and particularly, chemoresistant clones) are highly motile with behavior that is seemingly independent from specific microenvironments .…”

Metabolism as master of hematopoietic stem cell fate

“…However, tracking the division pattern of individual LSCs has proved challenging, and the development of new single-cell assay techniques is critical to achieving a better understanding of the molecular basis of LSC fate choice [116, 117]. Identifying the key metabolic cues that control LSC fate and maintain stemness upon division could yield effective targets in strategies to enhance LSC commitment, and will, therefore, have clear clinical importans.…”

Microscopy lights up stem cells in action

“…In one image, she showed red leukemia cells competing with healthy stem cells and other hematopoietic cells in glowing yellow, all within a network of teal blood vessels. Based on this and other observations, she next showed that by preserving the niche environment with deferoxamine, a drug that increased bone marrow vasculature, she could improve stem cell survival (5).…”

“…Lo Celso recently discovered that in a mouse model of acute myeloid leukemia, a cancer of the blood and bone marrow, cancer cells damaged blood vessels within the bone marrow, where stem cells reside (5). With that niche destroyed, the stem cells couldn't receive the signals that trigger proper differentiation.…”