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Leukemia. 2010 Apr;24(4):806-12. doi: 10.1038/leu.2010.2. Epub 2010 Feb 4.

NF-kappaB activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia.

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  • 1Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Abstract

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-kappaB was identified as a mechanism for IFN beta resistance, and inhibition of NF-kappaB activity in resistant cells sensitized cells to IFN beta. IFN beta combined with agents that inhibit NF-kappaB could have therapeutic potential in the treatment of children with mixed lineage leukemia subtype ALL.

PMID:
20130599
[PubMed - indexed for MEDLINE]

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