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

L. Tracey, C. J. Streck, Ziyun Du, Regan Williams, Lawrence Pfeffer, A. C. Nathwani, A. M. Davidoff

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)806-812
Number of pages7
JournalLeukemia
Volume24
Issue number4
DOIs
StatePublished - Jan 1 2010

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Interferons
Leukemia
Dependovirus
Hematologic Neoplasms
Therapeutics
Half-Life
Recurrence
Genes

All Science Journal Classification (ASJC) codes

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia. / Tracey, L.; Streck, C. J.; Du, Ziyun; Williams, Regan; Pfeffer, Lawrence; Nathwani, A. C.; Davidoff, A. M.

In: Leukemia, Vol. 24, No. 4, 01.01.2010, p. 806-812.

Research output: Contribution to journalArticle

Tracey, L. ; Streck, C. J. ; Du, Ziyun ; Williams, Regan ; Pfeffer, Lawrence ; Nathwani, A. C. ; Davidoff, A. M. / NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia. In: Leukemia. 2010 ; Vol. 24, No. 4. pp. 806-812.
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AU - Pfeffer, Lawrence

AU - Nathwani, A. C.

AU - Davidoff, A. M.

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