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

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.