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VE-cadherin Regulates Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Sensitivity to Apoptosis

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Cancer Microenvironment

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.

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Acknowledgements

This work was supported, in part, by NIH RO1HL056888 (LFG), NIH RO1CA134573 (LFG), and NIH P20 RR016440 (LFG). Image acquisition and data analysis were completed in the WVU Microscope Imaging Facility. Flow cytometry experiments were performed in the West Virginia University Flow Cytometry Core Facility, which is supported in part by NIH grants P20 RR106440 and RR020866. Immunohistochemical analysis was performed by the Pathology Core Facility.

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Authors and Affiliations

  1. Cancer Cell Biology Program, West Virginia University, School of Medicine, Morgantown, WV, 26506, USA

    Heather O’Leary, Stephen M. Akers & Laura F. Gibson

  2. Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, School of Medicine, P.O. Box 9300, Morgantown, WV, 26506, USA

    Heather O’Leary, Stephen M. Akers, Debra Piktel, James E. Fortney, Karen H. Martin, Michael Craig & Laura F. Gibson

  3. Department of Microbiology, Immunology and Cell Biology, West Virginia University, School of Medicine, Morgantown, WV, 26506, USA

    Laura F. Gibson

  4. Department of Pediatrics, West Virginia University, School of Medicine, Morgantown, WV, 26506, USA

    Cheryl Walton

  5. Department of Neurobiology and Anatomy, West Virginia University, School of Medicine, Morgantown, WV, 26506, USA

    Karen H. Martin

  6. Department of Pathology, West Virginia University, School of Medicine, Morgantown, WV, 26506, USA

    James Coad

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  1. Heather O’Leary
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  9. Laura F. Gibson
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Correspondence to Laura F. Gibson.

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O’Leary, H., Akers, S.M., Piktel, D. et al. VE-cadherin Regulates Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Sensitivity to Apoptosis. Cancer Microenvironment 3, 67–81 (2010). https://doi.org/10.1007/s12307-010-0035-6

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