Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Int J Hematol. 2013 Aug;98(2):153-7. doi: 10.1007/s12185-013-1368-y. Epub 2013 May 21.
The NOTCH and nuclear factor kappa B (NF-κB) pathways are both constitutively activated in Chronic Lymphocytic Leukemia (CLL). We first described the NOTCH1 PEST domain mutation in a CLL subgroup, but the activation of the NOTCH pathway in NOTCH1-unmutated cases remains unexplained. Here, we investigated whether genetic lesions in the NF-κB/NOTCH loop might support the NOTCH activation status by sequencing negative (TNFAIP3/A20) and positive (TRAF2, TRAF5, TNFRSF11A/RANK, MAP3K7/TAK1, and CARD11) regulators of NF-κB together with NF-κB targets on the NOTCH pathway, the NOTCH ligands Jagged1 and Jagged2, in CLL patients. The sequence analysis revealed four missense mutations for A20, TRAF2, TRAF5 and RANK1 genes, all causing a change in amino acid group from polar to non-polar, but functional domains were not involved. Specific predictive software analyses confirmed that the amino acid changes have a low-functional impact on the protein. Our results show that in CLL, NF-κB regulators and Jagged are both unmutated, suggesting that the Jagged-mediated interplay between NF-κB and NOTCH is independent of genetic lesions.
NOTCH 和核因子 kappa B（NF-κB）通路在慢性淋巴细胞白血病（CLL）中均呈持续激活状态。我们首先在 CLL 亚组中描述了 NOTCH1 PEST 结构域突变，但 NOTCH1 未突变病例中 NOTCH 通路的激活仍未得到解释。在这里，我们通过测序负向（TNFAIP3/A20）和正向（TRAF2、TRAF5、TNFRSF11A/RANK、MAP3K7/TAK1 和 CARD11）调节 NF-κB 的基因病变，以及 NOTCH 通路中的 NF-κB 靶点、NOTCH 配体 Jagged1 和 Jagged2，来研究 NF-κB/NOTCH 循环中的遗传病变是否可能支持 NOTCH 激活状态。在 CLL 患者中。序列分析显示 A20、TRAF2、TRAF5 和 RANK1 基因均有四个错义突变，均导致氨基酸组从极性变为非极性，但不涉及功能域。特定的预测软件分析证实，氨基酸变化对蛋白质的功能影响较小。我们的结果表明，在 CLL 中，NF-κB 调节因子和 Jagged 均未突变，表明 Jagged 介导的 NF-κB 和 NOTCH 之间的相互作用独立于遗传病变。
