打开APP

Blood:PTPN22激活AKT促进白血病细胞生存

  1. AKT
  2. PTPN22
  3. 白血病

来源:生物谷 2012-11-18 23:29

磷酸酶PTPN22多态性变异已与多种自身免疫性疾病风险增加有关。近日,一项刊登在Blood杂志上的研究表明,PTPN22在慢性淋巴细胞白血病(CLL)中也过度表达。 慢性淋巴细胞白血病属慢性淋巴细胞恶性克隆性疾病。多起源于B细胞的恶性转化,淋巴细胞分化受阻于未成熟阶段,易伴发自身免疫病和低丙球蛋白血症。

磷酸酶PTPN22多态性变异已与多种自身免疫性疾病风险增加有关。近日,一项刊登在Blood杂志上的研究表明,PTPN22在慢性淋巴细胞白血病(CLL)中也过度表达。

慢性淋巴细胞白血病属慢性淋巴细胞恶性克隆性疾病。多起源于B细胞的恶性转化,淋巴细胞分化受阻于未成熟阶段,易伴发自身免疫病和低丙球蛋白血症。

研究证实,过度表达的PTPN22通过阻断B细胞受体(BCR)负调控细胞生存的信号通路,显著抑制抗原诱导的早期白血病细胞凋亡。更重要的是,该研究发现 PTPN22正向调节抗凋亡激酶Akt,Akt提供一个强大的刺激信号促进抗原诱导的白血病细胞生存。

总的来说,这些数据表明,PTPN22过度的表达对白血病细胞来说是一种保护机制,能使自身抗原激活的白血病细胞逃避死亡,提示蛋白激酶PKC抑制剂作用于PTPN22可用于治疗白血病。(生物谷:Bioon.com)

Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT

Roberto Negro, Stefania Gobessi, Pablo G. Longo, Yantao He, Zhong-Yin Zhang, Luca Laurenti, and Dimitar G. Efremov

A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes. We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells. This selective uncoupling of AKT from other downstream BCR signaling pathways is a result of inhibition of a negative regulatory circuit involving LYN, CD22, and SHIP. Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli. Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.

版权声明 本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。

87%用户都在用生物谷APP 随时阅读、评论、分享交流 请扫描二维码下载->