Title: Novel in vivo model of inducible multidrug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11) Authors
Submitted to: Cancer Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 22, 2010
Publication Date: October 1, 2010
Citation: Zunino, S.J., Storms, D.H., Ducore, J. 2010. Novel in vivo model of inducible multidrug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11). Cancer Letters. 296:49-54. Interpretive Summary: Resistance to drugs used to treat leukemia is the greatest obstacle to finding a cure for this disease. Infant leukemia are high-risk leukemias that have a poor prognosis for survival and are particularly resistant to drug therapies after relapse. In this study, we have used a cell line that was established from a 5 year old female with relapsed leukemia. We injected the leukemia into mice that do not have an intact immune system, and then treated the mice with different substances, including natural food-derived chemicals. During our study, we found that the leukemia cells became resistant to treatment with the drug vincristine, which is used in the clinic for treating pediatric leukemia. We analyzed part of the reason for this resistance and found that the leukemia cells began producing a protein called P-glycoprotein. P-glycoprotein acts to pump out different drugs from the leukemia cells, so that the drug cannot kill these cells. The results of this study describe a novel model for studying the mechanisms involved in drug resistance in high-risk infant leukemia cells and may be very useful for testing novel drugs that can overcome this drug resistance. Overcoming drug resistance in this type of leukemia will be critical for more successful treatment and prevention strategies in the future.
Technical Abstract: Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is found in 60-85% of infants with ALL and is classified as high-risk due to the generally poor prognosis for survival. Using the SEM cell line established from a patient with t(4;11) ALL, we evaluated the resistance of these cells to the chemotherapeutic agent vincristine in the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. SEM cells were injected into the tail vein and the peripheral mouse blood monitored for human CD19+ cells by flow cytometry. Once engraftment was observed mice were injected intraperitoneally with phosphate-buffered saline (PBS) as a control, or vincristine at a concentration of 0.5 mg/kg body weight three times per week. The levels of P-glycoprotein (PgP) on engrafted CD19+ SEM cells were analyzed by flow cytometry. SEM cells had no detectable level of PgP under cell culture conditions or when engrafted into mice that were treated with PBS. However, PgP expression was induced 3-fold by treatment of engrafted mice with vincristine. Survival curves showed that leukemia cell growth and subsequent death was initially delayed in the vincristine-treated mice, but the mice eventually succumbed to disease. These data describe a novel inducible model for investigating multidrug resistance mechanisms in high risk ALL with the t(4;11) chromosomal translocation.