CALming Down T Cell Acute Leukemia译文.docVIP

CALming Down T Cell Acute Leukemia 沉静的t细胞急性白血病 Class I phosphoinositide 3-kinase (PI3K) activate fundamental pathways controlling survival,proliferation, and metabolism and thus represent crucial players in cancer development. Despite activating similar signaling cascades, the four human class I PI3Ks, each of which is composed of a regulatory subunit and one of the four p110 catalytic subunits (p110a, b, g, and d), show nonredundant roles in oncogenesis. For example, PIK3CA, the gene encoding p110a,is frequently mutated in cancers originating from different organs, including the mammary gland, colon, prostate, and brain(Wongetal.,2010).Onthecontrary, the p110b isoform does not accumulate mutations but plays a critical role in specific tumors, such as PTEN-deficient (Jia et al., 2008) or ErbB2-driven (Ciraolo et al., 2008) cancers. Similarly, the leukocyte-specific p110d isoform is usually intact in human cancers, yet it drives B cell malignancies including chronic lymphocytic leukemia and mantle cell lymphoma (So and Fruman, 2012). The fourth PI3K catalytic isoform, p110g,ismainlyexpressedinleukocytes, and its role in cancer is only now starting to emerge. In white blood cells, p110g usually drives G protein coupled receptor (GPCR)-mediated responses and shapes various forms of inflammatory reactions bycontrollingmacrophageandneutrophil migration to chemotactic cues (Ghigo et al., 2010). Similar to p110d, p110g is also highly expressed in B and T lymphocytes but with a role considered minor so far, probably not affecting trafficking but rather specific differentiation steps. In T cell development, p110g and p110d together control the b selection process, allowing thymocytes to mature to the I级磷酸肌醇3激酶（PI3K）的激活控制生存，增殖和代谢的基本途径，因此，代表在癌症发展的关键球员。尽管类似的信号转导通路的激活，四个人类I类PI3Ks，其中每一个调节亚基组成四个P110催化亚基（p110a，B，G，D），表明在肿瘤发生的非冗余的作用。PIK3CA，基因编码p110a的，例如，经常来自不同的器官，包括乳腺，结肠癌，前列腺癌，和大脑（Wongetal.，2010）的癌症突变。相反，p110b亚型不积累突变，但在特定的肿瘤，如PTEN基因缺陷（佳等，2008）或ErbB2驱动（Ciraolo等，2008）癌症，起着至关重要的作用。同样，白