NF-κB 激活介导 MLL 重排急性淋巴细胞白血病对 IFNβ的耐药性。
NF-kappaB activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia.
机构信息
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
出版信息
Leukemia. 2010 Apr;24(4):806-12. doi: 10.1038/leu.2010.2. Epub 2010 Feb 4.
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.
摘要
急性淋巴细胞白血病（ALL）伴 t（4；11）易位与预后极差相关；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）在治疗实体瘤和血液系统恶性肿瘤方面显示出良好的效果，尽管半衰期短和大剂量相关的毒性限制了其临床应用。为了克服这些限制，我们使用腺相关病毒（AAV）介导的表达研究了通过连续、基因转移介导的 IFNβ传递对伴有 t（4；11）易位的 ALL 细胞的影响。我们发现，这种 IFNβ 传递方法可导致小鼠模型中白血病完全缓解。然而，白血病细胞最终对 IFNβ产生耐药性，并观察到复发。NF-κB 的激活被确定为 IFNβ 耐药的一种机制，并且在耐药细胞中抑制 NF-κB 活性使细胞对 IFNβ敏感。IFNβ 联合抑制 NF-κB 的药物在治疗混合谱系白血病亚型 ALL 的儿童中可能具有治疗潜力。
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