title: Activation of the vascular niche supports leukemic progression and resistance to chemotherapy.
abstract: Understanding the intricate cellular components of the bone marrow microenvironment can lead to the discovery of novel extrinsic factors that are responsible for the initiation and progression of leukemic disease. We have shown that endothelial cells (ECs) provide a fertile niche that allows for the propagation of primitive and aggressive leukemic clones. Activation of the ECs by vascular endothelial growth factor (VEGF)-A provides cues that enable leukemic cells to proliferate at higher rates and also increases the adhesion of leukemia to ECs. Vascular endothelial growth factor A-activated ECs decrease the efficacy of chemotherapeutic agents to target leukemic cells. Inhibiting VEGF-dependent activation of ECs by blocking their signaling through VEGF receptor 2 increases the susceptibility of leukemic cells to chemotherapy. Therefore, the development of drugs that target the activation state of the vascular niche could prove to be an effective adjuvant therapy in combination with chemotherapeutic agents.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Poulos
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gars
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gutkin
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Kloss
authors.affiliation: Angiocrine Bioscience, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ginsberg
authors.affiliation: Division of Hematology and Medical Oncology, Leukemia and Bone Marrow Failure Program, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Butler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D002999:Clone Cells; D018920:Coculture Techniques; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2