title: VE-cadherin Regulates Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Sensitivity to Apoptosis.
abstract: The mechanisms by which the bone marrow microenvironment regulates tumor cell survival are diverse. This study describes the novel observation that in addition to Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cell lines, primary patient cells also express Hypoxia Inducible Factor-2α (HIF-2α) and Vascular Endothelial Cadherin (VE-cadherin), which are regulated by Abl kinase. Tumor expression of the classical endothelial protein, VE-cadherin, has been associated with aggressive phenotype and poor prognosis in other models, but has not been investigated in hematopoietic malignancies. Targeted knockdown of VE-cadherin rendered Ph+ ALL cells more susceptible to chemotherapy, even in the presence of bone marrow stromal cell (BMSC) derived survival cues. Pre-treatment of Ph+ ALL cells with ADH100191, a VE-cadherin antagonist, resulted in increased apoptosis during in vitro chemotherapy exposure. Consistent with a role for VE-cadherin in modulation of leukemia cell viability, lentiviral-mediated expression of VE-cadherin in Ph- ALL cells resulted in increased resistance to treatment-induced apoptosis. These observations suggest a novel role for VE-cadherin in modulation of chemoresistance in Ph+ ALL.
authors.forename: Heather
authors.initials: H
authors.lastname: O'Leary
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Akers
authors.forename: Debra
authors.initials: D
authors.lastname: Piktel
authors.forename: Cheryl
authors.initials: C
authors.lastname: Walton
authors.forename: James E
authors.initials: JE
authors.lastname: Fortney
authors.forename: Karen H
authors.initials: KH
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Craig
authors.forename: James
authors.initials: J
authors.lastname: Coad
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson