Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells
Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells
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DOI：
10.1182/blood-2003-07-2193
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发表时间：
2004-06-01
期刊：
影响因子：
20.3
通讯作者：
Fruman, DA
中科院分区：
文献类型：
--
作者：
Kharas, MG;Deane, JA;Fruman, DA
BCR-ABL和v-ABL是Abl酪氨酸激酶的致癌形式，可引起小鼠和人类的白血病。ABL癌基因触发多种信号通路，其对转化的贡献在细胞类型中不同。磷酸肌醇3-激酶（P13 K）的激活对于某些细胞类型中的ABL依赖性增殖和存活至关重要，并且全局P13 K抑制剂可以增强Abl激酶抑制剂伊马替尼的抗白血病作用。虽然BCR-ABL诱导的人白血病中有相当一部分是B细胞起源的，但对ABL癌基因转化的B系细胞中P13 K信号传导机制知之甚少。在这里，我们发现I-A类P13 K的激活和下游FOXO转录因子的失活对于由v-ABL或BCR-ABL转化的小鼠pro/pre-B细胞的存活是必不可少的。对缺乏单个P13 K基因的小鼠的分析表明，Pik 3r 1基因的产物有助于BCR-ABL的转化效率。这些发现确立了P13 K信号在B-ABL中的作用。ABL癌基因的谱系转化。(C)2004年，美国血液学会。
BCR-ABL and v-ABL are oncogenic forms of the Abl tyrosine kinase that can cause leukemias in mice and humans. ABL oncogenes trigger multiple signaling pathways whose contribution to transformation varies among cell types. Activation of phosphoinositide 3-kinase (P13K) is essential for ABL-dependent proliferation and survival in some cell types, and global P13K inhibitors can enhance the antileukemia effects of the Abl kinase inhibitor imatinib. Although a significant fraction of BCR-ABL-induced human leukemias are of B-cell origin, little is known about P13K signaling mechanisms in B-lineage cells transformed by ABL oncogenes. Here we show that activation of class I-A P13K and downstream inactivation of FOXO transcription factors are essential for survival of murine pro/pre-B cells transformed by v-ABL or BCR-ABL. In addition, analysis of mice lacking individual P13K genes indicates that products of the Pik3r1 gene contribute to transformation efficiency by BCR-ABL. These findings establish a role for P13K signaling in B-lineage transformation by ABL oncogenes. (C) 2004 by The American Society of Hematology.