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 Blood, 1 November 2007, Vol. 110, No. 9, pp. 3334-3344.
Prepublished online as a Blood First Edition Paper on August 13, 2007; DOI 10.1182/blood-2007-01-068122.

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NEOPLASIA

Ph+/VE-cadherin+ identifies a stem cell–like population of acute lymphoblastic leukemia sustained by bone marrow niche cells

Lin Wang1, Heather O'Leary2, James Fortney1, and Laura F. Gibson1,3

1 Department of Pediatrics, 2 Department of Microbiology and Immunology, and 3 Mary Babb Randolph Cancer Center, West Virginia University, School of Medicine, Morgantown

Although leukemic stem cells (LSCs) show 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 Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed 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 ß-catenin, and up-regulated 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 up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/ß-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.


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