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.