ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells
ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells
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DOI：
10.1182/blood-2003-01-0291
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发表时间：
2003-12-15
期刊：
影响因子：
20.3
通讯作者：
Ozato, K
中科院分区：
文献类型：
--
作者：
Tamura, T;Kong, HJ;Ozato, K
干扰素一致序列结合蛋白/干扰素调节因子8 （ICSBP/IRF-8）是一种控制髓细胞发育的转录因子。ICSBF-/-小鼠发展为慢性髓性白血病（CML）样综合征。对患者和小鼠模型的几项观察表明，ICSBP与CML的发病机制有关。在本文中，我们研究了ICSBP是否调节了CIVIL的致癌蛋白Bcr/Abl的促生长活性。当用p210 Bcr/Abl转化时，ICSBP-/-髓系祖细胞失去了对生长因子的依赖，在缺乏粒细胞-巨噬细胞集落刺激因子的情况下生长。当ICSBP异位表达时，Bcr/Abl转化的细胞完全停止生长并分化为成熟的功能巨噬细胞，而不抑制Bcr/Abl的激酶活性。ICSBP可显著抑制Bcr/Abl下游靶点c-Myc信使RNA （mRNA）的表达，这为生长阻滞提供了机制基础。对ICSBP/雌激素受体嵌合体的进一步分析表明，ICSBP对c-Myc的抑制是间接的，是由另一个基因介导的。我们发现Blimp-1和METS/PE1是这些细胞中激活的ICSBP的直接靶点，它们是有效的c-Myc抑制因子。与此一致，异位的Blimp-1抑制c-Myc表达并抑制细胞生长。这些结果表明，ICSBP通过激活干扰c-Myc通路的几个基因来抑制Bcr/ abl转化的髓系祖细胞的生长。(C) 2003年由美国血液病学会出版。
Interferon consensus sequence binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) is a transcription factor that controls myeloid cell development. ICSBF-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth-promoting activity of Bcr/Abl, the causal oncoprotein for CIVIL. When transformed with p210 Bcr/Abl, ICSBP-/- myeloid progenitor cells lost growth factor dependence and grew in the absence of granulocyte-macrophage colony-stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc messenger RNA (mRNA)expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed myeloid progenitor cells by activating several genes that interfere with the c-Myc pathway. (C) 2003 by The American Society of Hematology.