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NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia

Tracey, L; Streck, CJ; Du, Z; Williams, RF; Pfeffer, LM; Nathwani, AC; Davidoff, AM; (2010) NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia. Leukemia , 24 (4) pp. 806-812. 10.1038/leu.2010.2.

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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 Β (IFNΒ) 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 IFNΒ using adeno-associated virus (AAV)-mediated expression, on ALL cells with the t(4;11) translocation. We found that this method of IFNΒ delivery resulted in complete remission of leukemia in a murine model. However, leukemic cells eventually became resistant to IFNΒ and relapse was observed. Activation of NF-B was identified as a mechanism for IFNΒ resistance, and inhibition of NF-B activity in resistant cells sensitized cells to IFNΒ. IFNΒ combined with agents that inhibit NF-B could have therapeutic potential in the treatment of children with mixed lineage leukemia subtype ALL. © 2010 Macmillan Publishers Limited All rights reserved.

Type: Article
Title: NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia
DOI: 10.1038/leu.2010.2
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1336445
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