The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target
The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target
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DOI：
10.1182/blood-2007-11-125278
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Pepper, Chris
中科院分区：
文献类型：
--
作者：
Hewamana, Saman;Alghazal, Suhair;Pepper, Chris
在这项研究中，我们表征了核因子κ B （nf - κ B）亚基DNA在慢性淋巴细胞白血病（CLL）样本中的结合，并证明了基础和诱导nf - κ B的异质性。然而，所有病例的基础nf - κ B均高于正常B细胞。亚基分析显示，原代CLL细胞中存在p50、Rel A和c-Rel的DNA结合，Rel A DNA结合与体外存活相关（P = 0.01），白细胞计数高（P = 0.01），淋巴细胞倍增时间短（P = 0.01）。体外抗igm刺激后NF-kappa B诱导与体外存活（P < 0.001）和信号分子ZAP-70表达增加（P = 0.003）相关。根据这些数据，我们在54例CLL患者样本中评估了新的parthenolide类似物LC-1。LC-1在24小时后诱导所有样品的细胞凋亡，平均LD50为2.8 μ M；正常B细胞和T细胞对其凋亡作用的抗性明显增强（P < 0.001）。凋亡发生前，nf - κ B DNA结合明显丧失，对LC-1的敏感性与基础Rel - a DNA结合相关（P = 0.03, r(2) = 0.15）。此外，Rel A DNA结合与氟达拉滨敏感性呈负相关（P = 0.001, r(2) = 0.3），暗示Rel A与氟达拉滨耐药有关。综上所述，这些数据表明，rela是这种不治之症的一个极好的治疗靶点。
In this study, we characterized nuclear factor kappa B (NF-kappa B) subunit DNA binding in chronic lymphocytic leukemia (CLL) samples and demonstrated heterogeneity in basal and inducible NF-kappa B. However, all cases showed higher basal NF-kappa B than normal B cells. Subunit analysis revealed DNA binding of p50, Rel A, and c-Rel in primary CLL cells, and Rel A DNA binding was associated with in vitro survival (P = .01) with high white cell count (P = .01) and shorter lymphocyte doubling time (P = .01). NF-kappa B induction after in vitro stimulation with anti-IgM was associated with increased in vitro survival (P < .001) and expression of the signaling molecule ZAP-70 (P = .003). Prompted by these data, we evaluated the novel parthenolide analog, LC-1, in 54 CLL patient samples. LC-1 induced apoptosis in all the samples tested with a mean LD50 of 2.8 mu M after 24 hours; normal B and T cells were significantly more resistant to its apoptotic effects (P < .001). Apoptosis was preceded by a marked loss of NF-kappa B DNA binding and sensitivity to LC-1 correlated with basal Rel A DNA binding (P = .03, r(2) = 0.15). Furthermore, Rel A DNA binding was inversely correlated with sensitivity to fludarabine (P = .001, r(2) = 0.3), implicating Rel A in fludarabine resistance. Taken together, these data indicate that Rel A represents an excellent therapeutic target for this incurable disease.