NF-kappaB 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-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.
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
L
L
Tracey
C J
CJ
Streck
Z
Z
Du
R F
RF
Williams
L M
LM
Pfeffer
A C
AC
Nathwani
A M
AM
Davidoff
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D016899:Interferon-beta; D048031:JNK Mitogen-Activated Protein Kinases