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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3334-3344.
Prepublished online as a Blood First Edition Paper on July 16, 2007August 13, 2007; DOI 10.1182/blood-2007-01-068122.
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Submitted January 16, 2007
Accepted July 4, 2007
Ph+/VE-cadherin+ identifies a stem-cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells
Lin Wang, Heather O'Leary, James Fortney, and Laura F. Gibson*
Department of Pediatrics, West Virginia University, School of Medicine, Morgantown, WV, United States
Department of Microbiology & Immunology, West Virginia University, School of Medicine, Morgantown, WV, United States
Mary Babb Randolph Cancer Center, West Virginia University, School of Medicine, Morgantown, WV, United States
* Corresponding author; email: lgibson{at}hsc.wvu.edu.
Although leukemic stem cells (LSCs) demonstrate 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 Ph+ ALL cells co-expressing markers of endothelial cells (including VE-cadherin, PECAM-1 and Flk-1) and committed B-lineage progenitors. Following long-term co-culture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem cell markers, and demonstrated 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  -catenin and upregulated 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 upregulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify Bcr-abl/VE-cadherin/-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.
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