title: Functional integration of acute myeloid leukemia into the vascular niche.
abstract: Vascular endothelial cells are a critical component of the hematopoietic microenvironment that regulates blood cell production. Recent studies suggest the existence of functional cross-talk between hematologic malignancies and vascular endothelium. Here we show that human acute myeloid leukemia (AML) localizes to the vasculature in both patients and in a xenograft model. A significant number of vascular tissue-associated AML cells (V-AML) integrate into vasculature in vivo and can fuse with endothelial cells. V-AML cells acquire several endothelial cell-like characteristics, including the upregulation of CD105, a receptor associated with activated endothelium. Remarkably, endothelial-integrated V-AML shows an almost fourfold reduction in proliferative activity compared with non-vascular-associated AML. Primary AML cells can be induced to downregulate the expression of their hematopoietic markers in vitro and differentiate into phenotypically and functionally defined endothelial-like cells. After transplantation, these leukemia-derived endothelial cells are capable of giving rise to AML. These novel functional interactions between AML cells and normal endothelium along with the reversible endothelial cell potential of AML suggest that vascular endothelium may serve as a previously unrecognized reservoir for AML.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Devorah C
authors.initials: DC
authors.lastname: Goldman
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Madlambayan
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Leon
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Azzah Al
authors.initials: AA
authors.lastname: Masri
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Clark
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Asbaghi
authors.affiliation: Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.|Department of Pathology, Oregon Health & Sciences University, Portland, OR.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dunlap
authors.affiliation: Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.|Department of Pathology, Oregon Health & Sciences University, Portland, OR.
authors.forename: Guang
authors.initials: G
authors.lastname: Fan
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kovacsovics
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Amy
authors.initials: A
authors.lastname: Meacham
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Hamlin
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hromas
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Sciences University, Portland, OR.|Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR.
authors.forename: William H
authors.initials: WH
authors.lastname: Fleming
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D012008:Recurrence; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface