NF-kappaB activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia.
NF-kappaB activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia.
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DOI：
10.1038/leu.2010.2
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发表时间：
2010-04
期刊：
影响因子：
11.4
通讯作者：
Davidoff AM
中科院分区：
文献类型：
--
作者：
Tracey L;Streck CJ;Du Z;Williams RF;Pfeffer LM;Nathwani AC;Davidoff AM
携带t（4;11）易位的急性淋巴细胞白血病（ALL）预后极差，需要创新的治疗策略来提高目前30- 40%的5年生存率。干扰素β（IFNβ）在实体瘤和血液系统恶性肿瘤的治疗中显示出前景，尽管与高剂量相关的短半衰期和毒性限制了其临床用途。为了克服这些局限性，我们研究了使用腺相关病毒（AAV）介导表达的连续基因转移介导的IFNβ递送对具有t（4;11）易位的ALL细胞的影响。我们发现这种IFNβ递送方法在小鼠模型中导致白血病的完全缓解。然而，白血病细胞最终对IFNβ产生耐药性，并观察到复发。NF-κB的活化被确定为IFNβ抗性的机制，并且抗性细胞中NF-κB活性的抑制使细胞对IFNβ敏感。IFNβ联合NF-κB抑制剂可能对儿童混合系白血病亚型ALL具有治疗潜力。
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-κB was identified as a mechanism for IFNβ resistance, and inhibition of NF-κB activity in resistant cells sensitized cells to IFNβ. IFNβ combined with agents that inhibit NF-κB could have therapeutic potential in the treatment of children with mixed lineage leukemia subtype ALL.