Apolipoproteins from the microenvironment promote aggressive myeloid leukemia progression

Abstract

Abstract The bone marrow microenvironment consists of diverse cell populations, including mesenchymal stromal cells (MSCs), osteolineage cells, fibroblasts, and endothelial cells, all of which support hematopoietic stem cells. The interaction of stromal populations with their microenvironment is essential for sustaining normal development and homeostasis. Aggressive myeloid leukemias such as acute myeloid leukemia (AML), often exploit these interactions to promote their progression. Even with notable progress in targeted therapies, the survival rate for patients with AML is approximately 30%, underscoring the need to discover new regulators of disease progression. Work by us, and others, has identified that signals from the bone marrow microenvironment can be actionable vulnerabilities for therapeutic targeting of AML. Our recent temporal single-cell RNA-sequencing based analyses of the AML microenvironment identified signals from the expanding MSC niche, such as apolipoproteins, that may play a role in AML progression. Apolipoproteins are complexes that transport lipids such as triglycerides and cholesterol in the bloodstream, and act as ligands for receptors involved in lipid metabolism. They can also regulate disease growth by interacting with cell surface receptors expressed on AML cells. However, the role that apolipoproteins play in leukemia progression is not well understood. We find that MSCs from murine and human bone marrow have the highest apolipoprotein E (ApoE) expression. Importantly, our immunohistochemistry-based assays indicate that APOE protein expression increases in the human bone marrow stroma with AML progression. Consistent with a functional role of niche-derived APOE in supporting AML cell growth, our experiments show that inhibiting APOE expression in MSCs from AML patients can block the growth of co-cultured patient-matched leukemia cells. To investigate the impact of ApoE on AML progression in vivo, we used loss-of-function murine models of ApoE. Our data showing that murine leukemia growth is delayed in ApoE knockout mice as compared to wild-type controls suggests that microenvironmental ApoE is essential for in vivo leukemia progression. Mechanistically, our data suggest that the effect of ApoE on leukemia cell growth may be due to its effect on MAPK signaling. Collectively, our studies establish a key role of leukemia tumor microenvironment derived apolipoproteins on AML progression.