文章：

色素性干皮病B组蛋白结合位点的缺失会损害p210 BCR/ABL1的致白血病活性

Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity

原文发布日期：2013-08-16

DOI: 10.1038/bcj.2013.36

类型: Original Article

开放获取: 是

英文摘要：

Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB. Loss of XPB binding is associated with reduced expression of c-MYC and reduced transforming potential in ex-vivo clonogenicity assays, but does not affect nucleotide excision repair in lymphoid or myeloid cells. When examined in a bone marrow transplantation (BMT) model for chronic myelogenous leukemia, mice that express the mutant exhibit attenuated myeloproliferation and lymphoproliferation when compared with mice that express unmodified p210 BCR/ABL1. Thus, the mutant-transplanted mice show predominantly neutrophilic expansion and altered progenitor expansion, and have significantly extended lifespans. This was confirmed in a BMT model for B-cell acute lymphoblastic leukemia, wherein the majority of the mutant-transplanted mice remain disease free. These results suggest that the interaction between p210 BCR/ABL1 and XPB can contribute to disease progression by influencing the lineage commitment of lymphoid and myeloid progenitors.

摘要翻译： 

先前研究已证实，p210 BCR/ABL1与着色性干皮病B组（XPB）蛋白直接相互作用，且在表达p210 BCR/ABL1的细胞中XPB会发生酪氨酸磷酸化。本研究构建了一种无法与XPB结合的p210 BCR/ABL1突变体。该突变体具有正常激酶活性并能与GRB2相互作用，但不再使XPB发生磷酸化。XPB结合能力的缺失与c-MYC表达水平下降及体外克隆形成实验中转化潜能减弱相关，但不影响淋巴或髓系细胞的核苷酸切除修复功能。在慢性髓系白血病骨髓移植模型中发现，与表达未修饰p210 BCR/ABL1的小鼠相比，表达该突变体的小鼠表现出减弱的髓系增殖和淋巴增殖。因此，突变体移植小鼠主要表现为中性粒细胞扩增和祖细胞扩增模式改变，且寿命显著延长。这在B细胞急性淋巴细胞白血病的骨髓移植模型中得到进一步验证——大多数突变体移植小鼠均未发生疾病。这些结果表明，p210 BCR/ABL1与XPB的相互作用可通过影响淋巴系和髓系祖细胞的谱系定向分化，进而促进疾病进展。

原文链接：

Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity