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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromosomes, Human, Pair 11 / genetics
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Chromosomes, Human, Pair 4 / genetics
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Dependovirus / genetics
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Drug Resistance, Neoplasm
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Electrophoretic Mobility Shift Assay
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Flow Cytometry
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Gene Expression Regulation, Leukemic*
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Gene Rearrangement*
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Humans
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Interferon-beta / pharmacology*
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mice
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Mice, SCID
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Translocation, Genetic
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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NF-kappa B
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RNA, Messenger
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Myeloid-Lymphoid Leukemia Protein
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Interferon-beta
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JNK Mitogen-Activated Protein Kinases