title: Ph+/VE-cadherin+ identifies a stem cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells.
abstract: Although leukemic stem cells (LSCs) show a symbiotic relationship with bone marrow microenvironmental niches, the mechanism by which the marrow microenvironment contributes to self-renewal and proliferation of LSCs remains elusive. In the present study, we identified a unique subpopulation of Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed endothelial sprouting. Gene expression profiles of LSCs were altered in the presence of stromal cell contact. Stromal cell contact promoted leukemic cell VE-cadherin expression, stabilized beta-catenin, and up-regulated Bcr-abl fusion gene expression. Our study indicates that these specific tumor cells are uniquely positioned to respond to microenvironment-derived self-renewing and proliferative cues. Ph(+)/VE-cadherin(+) tumor subpopulation circumvents the requirement of exogenous Wnt signaling for self-renewal through stromal cell support of leukemic cell VE-cadherin expression and up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/beta-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.
authors.affiliation: Department of Pediatrics, and Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Heather
authors.initials: H
authors.lastname: O'Leary
authors.forename: James
authors.initials: J
authors.lastname: Fortney
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D015820:Cadherins; D046988:Proteasome Endopeptidase Complex; D051153:Wnt Proteins; D051176:beta Catenin; D000099152:Cadherin 5