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Acute Leukemias

Increased resistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblastic leukemia cells

Leukemia volume 21, pages 1189–1197 (2007)Cite this article

Abstract

In leukemia patients, resistance to drug treatment develops while the malignant cells can interact with and derive support from their microenvironment, such as bone marrow stroma. To model this process, lymphoblastic leukemia cells from BCR/ABL transgenic mice were treated with the farnesyltransferase inhibitor (FTI) SCH66336 while in coculture with primary mouse embryonic fibroblasts. Coculture with fibroblasts allowed the outgrowth of a subpopulation of drug-resistant lymphoblasts that expressed N-cadherin, a cell–cell adhesion protein that normally is only expressed on specific cell types, including hematopoietic stem cells and fibroblasts. N-cadherin expression promoted increased adhesion of the lymphoblasts to the fibroblasts. Importantly, de novo expression of N-cadherin in parental nonexpressing lymphoblasts using lentiviral transduction increased the ability of the cells to survive FTI treatment. We conclude that FTI drug treatment of Bcr/Abl-positive lymphoblastic leukemia cells that are in contact with a defined microenvironment induces the selective survival of a more primitive subpopulation of leukemia cells that expresses N-cadherin. Experimental drug treatment of cancer cells in model systems that include a microenvironment may reveal novel molecules that contribute to drug resistance and may aid in the design of specific therapies to eradicate more primitive cells.

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Acknowledgements

We thank Didier Trono for PAX2 and envelope pMD2G plasmids and the CHLA Vector core for pCCL-PGK-EGFP, as well as Young Jin Cho and Jess Cunnick for helpful suggestions. We thank the FACS Core and the Image Core of the CHLARI for assistance with FACS analysis and imaging and Samuel Wu, Director of CHLA Clinical Cytogenetics, for the karyotype analysis. This study was supported by PHS NIH grant CA 50248 (NH), the TJ Martell Foundation (JG and NH) and the Kenneth T. and Eileen L. Norris Foundation (BZ, JG).

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  1. B Zhang

    Present address: 2Current address: Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA,

Authors and Affiliations

  1. Division of Hematology/Oncology, Section of Molecular Carcinogenesis, Saban Research Institute, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    B Zhang, J Groffen & N Heisterkamp

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Correspondence to N Heisterkamp.

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Supplementary Information accompanies the paper on the Leukemia Web site (http://www.nature.com/leu)

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Zhang, B., Groffen, J. & Heisterkamp, N. Increased resistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblastic leukemia cells. Leukemia 21, 1189–1197 (2007). https://doi.org/10.1038/sj.leu.2404667

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