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Research Articles: Therapeutics, Targets, and Development

Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells

¹ Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute; ² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital; ³ Department of Medicine, Harvard Medical School, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Ellen Weisberg, Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3575; Fax: 617-632-4388. E-mail: Ellen_Weisberg{at}dfci.harvard.edu

Abstract

Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma-leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL-positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow–associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells. [Mol Cancer Ther 2008;7(5):1121–9]

Grant support: NIH grants CA66996, CA36167, and DK50654 and Leukemia and Lymphoma Society Specialized Center of Research Award. C. Mitsiades, R. Stone, A.L. Kung, and J.D. Griffin have a financial interest with Novartis Pharma AG.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary data for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/26/07; revised 1/ 7/08; accepted 1/23/08.