磷酸酶PTPN22多態(tài)性變異已與多種自身免疫性疾病風(fēng)險(xiǎn)增加有關(guān),。近日，一項(xiàng)刊登在Blood雜志上的研究表明,，PTPN22在慢性淋巴細(xì)胞白血?。–LL）中也過度表達(dá)。
慢性淋巴細(xì)胞白血病屬慢性淋巴細(xì)胞惡性克隆性疾病,。多起源于B細(xì)胞的惡性轉(zhuǎn)化,，淋巴細(xì)胞分化受阻于未成熟階段，易伴發(fā)自身免疫病和低丙球蛋白血癥,。
研究證實(shí),，過度表達(dá)的PTPN22通過阻斷B細(xì)胞受體（BCR）負(fù)調(diào)控細(xì)胞生存的信號(hào)通路，顯著抑制抗原誘導(dǎo)的早期白血病細(xì)胞凋亡,。更重要的是,，該研究發(fā)現(xiàn) PTPN22正向調(diào)節(jié)抗凋亡激酶Akt，Akt提供一個(gè)強(qiáng)大的刺激信號(hào)促進(jìn)抗原誘導(dǎo)的白血病細(xì)胞生存,。
總的來說,，這些數(shù)據(jù)表明,，PTPN22過度的表達(dá)對(duì)白血病細(xì)胞來說是一種保護(hù)機(jī)制，能使自身抗原激活的白血病細(xì)胞逃避死亡,，提示蛋白激酶PKC抑制劑作用于PTPN22可用于治療白血病,。（生物谷：Bioon.com）
doi:10.1182/blood-2012-01-403162
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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.
