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.