Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2
Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2
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DOI：
10.1182/blood-2003-08-2970
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发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Neubauer, A
中科院分区：
文献类型：
--
作者：
Burchert, A;Cai, D;Neubauer, A
BCR/ABL是慢性髓性白血病（CML）的致病基因畸变。干扰素（IFN）一致序列结合蛋白（ICSBP）是干扰素调节因子（IRF）家族中ifγ诱导的转录因子，缺乏表达的小鼠会患上类似于人类CIVIL的疾病。越来越多的证据表明ICSBP在CML发病机制中的作用。然而，潜在的机制在很大程度上是未知的。通过在野生型和BCR/ abl转化的32D细胞（32D/wt和32D/BA）中稳定和有条件地表达ICSBP，我们发现ICSBP在体内抑制BCR/ abl介导的白血病发生。此外，ICSBP还覆盖了BCR/ abl介导的形态学改变、化疗和伊马替尼耐药性，以及BCR/ abl诱导的分化抑制。ICSBP的一些作用可能部分解释为ICSBP介导的bcl-2在转录和蛋白水平上的抑制，bcl-2是BCR/ABL的主要抗凋亡靶点。通过报告基因检测和电泳迁移率转移检测，我们发现bcl-2启动子活性通过含有2个ICSBP响应元件的片段被ICSBP抑制。体内实验证实ICSBP与bcl-2表达呈负相关。总之，我们的研究结果表明，ICSBP通过下调bcl-2拮抗BCR/ABL，暗示ICSBP在CML发病机制中的核心作用，以及克服bcl-2依赖性肿瘤耐药的治疗靶点。(C) 2004年由美国血液病学会出版。
BCR/ABL is the causative genetic aberration in chronic myelogenous leukemia (CML). Mice lacking expression of the interferon (IFN) consensus sequence binding protein (ICSBP), an IFNgamma-inducible transcription factor of the interferon regulatory factor (IRF) family, develop a disease similar to human CIVIL. Mounting evidence suggests a role for ICSBP in the pathogenesis of CML. However, the underlying mechanisms are largely unknown. By stable and conditional expression of ICSBP in wild-type and BCR/ABL-transformed 32D cells (32D/wt and 32D/BA), we found that ICSBP inhibited BCR/ABL-mediated leukemo-genesis in vivo. Moreover, ICSBP also overrode BCR/ABL-mediated morphology changes, chemotherapy, and imatinib resistance, as well as BCR/ABL-induced repression of differentiation. Some of these ICSBP effects may be explained in part by an ICSBP-mediated repression of bcl-2, a major antiapoptotic target of BCR/ABL, on transcriptional and protein level. Using reporter gene assays and electrophoretic mobility shift assays we identified that the bcl-2 promoter activity was inhibited by ICSBP by way of a fragment containing 2 characteristic ICSBP-responsive elements. An inverse correlation between ICSBP and bcl-2 expression was confirmed in vivo. Collectively, our findings suggest that ICSBP antagonizes BCR/ABL by down-regulation of bcl-2 and implicates a central role for ICSBP in the pathogenesis of CML, as well as a therapeutic target to overcome drug resistance in bcl-2-dependent tumors. (C) 2004 by The American Society of Hematology.