NF-kappa B activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) harboring the t(4;11) translocation is associated with a very poor prognosis; innovative treatment strategies are required to improve the current 5-year survival rate of 30-40%. Interferon beta (IFN beta) has shown promise in the treatment of both solid and hematologic malignancies, although the short half-life and toxicity associated with high doses have limited its clinical utility. To overcome these limitations, we investigated the effect of continuous, gene transfer-mediated delivery of IFN beta using adeno-associated virus (AAV)-mediated expression, on ALL cells with the t(4; 11) translocation. We found that this method of IFN beta delivery resulted in complete remission of leukemia in a murine model. However, leukemic cells eventually became resistant to IFN beta and relapse was observed. Activation of NF-kappa B was identified as a mechanism for IFN beta resistance, and inhibition of NF-kappa B activity in resistant cells sensitized cells to IFN beta. IFN beta combined with agents that inhibit NF-kappa B could have therapeutic potential in the treatment of children with mixed lineage leukemia subtype ALL. Leukemia (2010) 24, 806-812; doi: 10.1038/leu.2010.2; published online 4 February 2010