Endothelial cell derived angiocrine support of acute myeloid leukemia targeted by receptor tyrosine kinase inhibition

Abstract

In acute myeloid leukemia (AML), refractory disease is a major challenge and the leukemia microenvironment may harbor refractory disease. Human AML cell lines KG-1 and HL-60 expressed receptors also found on endothelial cells (ECs) such as VEGFRs, PDGFRs, and cKit. When human AML cells were co-cultured with human umbilical vein endothelial cells (HUVECs) and primary bone marrow endothelial cell (BMECs), the AML cells were more resistant to cytarabine chemotherapy, even in transwell co-culture suggesting angiocrine regulation. Primary BMECs secreted significantly increased levels of VEGF-A and PDGF-AB after exposure to cytarabine. Pazopanib, a receptor tyrosine kinase inhibitor (RTKI) of VEGFRs, PDGFRs, and cKit, removed EC protection of AML cells and enhanced AML cell sensitivity to cytarabine. Xenograft modeling showed significant regression of AML cells and abrogation of BM hypervascularity in RTKI treated cohorts. Together, these results show direct cytotoxicity of RTKIs on AML cells and reversal of EC protection. Combining RTKIs with chemotherapy may serve as promising therapeutic strategy for patients with AML.

Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia

“…In a complementary study, the abnormal secretion of these angiocrine factors potently inhibited the apoptosis of leukemia cells and promoted their growth via paracrine mechanisms [31]. However, inhibition of angiocrine receptors abrogated chemotherapy-induced angiogenesis and successfully reversed the resistance of AML [32].…”

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

“…Supporting this observation, another T‐ALL study showed a significant reduction in leukemia upon CXCL12 deletion from ECs , suggesting an important role for EC derived CXCL12 in leukemic survival. Studies have shown ECs to impart chemoresistance to AML cells in close proximity , while pharmacological inhibition of the endothelial cell derived angiocrine support significantly impeded leukemic growth . The work in aggregate shows that leukemia drastically affects the bone marrow compartment, changing both structural composition and function while hastening leukemic progression.…”

XBP1 splicing triggers miR-150 transfer from smooth muscle cells to endothelial cells via extracellular vesicles

“…PDGF is another important growth factor for angiogenesis under ischemia. It can be induced from ECs in response to ischemia or other stimulus 48 49 50 , which in turn activates medial SMCs proliferation and migration, leading to vessel wall remodelling 51 52 . During this process, XBP1 splicing plays an important role 17 .…”