Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder

作     者：Hao, SX Ren, RB 

作者机构：Brandeis Univ Rosenstiel Basic Med Sci Res Ctr Dept Biol Waltham MA 02454 USA 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：2000年第20卷第4期

页      面：1149-1161页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NCI NIH HHS [CA68008  R01 CA068008] Funding Source: Medline 

主　　题：抗代谢药 抗肿瘤/药理学 B淋巴细胞/病理学 碱基序列 骨髓移植 集落形成单位测定 共有序列 DNA引物/遗传学 疾病模型 动物 减量调节 氟尿嘧啶/药理学 基因 abl 血细胞生成/遗传学 干扰素调节因子类 干扰素类/代谢 白血病 髓系 慢性 BCR-ABL阳性/遗传学 白血病 髓系 慢性 BCR-ABL阳性/代谢 白血病 髓系 慢性 BCR-ABL阳性/病理学 淋巴组织增殖性疾病/病因学 淋巴组织增殖性疾病/遗传学 小鼠 近交BALBC 骨髓增殖性疾病/遗传学 骨髓增殖性疾病/预防和控制 阻遏蛋白质类/遗传学 阻遏蛋白质类/代谢 易位 遗传 动物 人类 男(雄)性 小鼠 

摘      要：Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML are associated with the (9;22) chromosome translocation that generates the bcr-abl chimeric gene. Alpha interferon (IFN-alpha) treatment induces hematological remission and prolongs life in 75% of CML patients in the chronic phase. It has been shown that mice deficient in interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral transduction efficiently induces a myeloproliferative disease in mice resembling human CML. To directly test whether icsbp can function as a tumor suppressor gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using this murine model for CML. We found that expression of the ICSBP protein was significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU-treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo. Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B-lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU-treated donors were used, indicating that ICSBP has a specific antitumor activity toward myeloid neoplasms. We also found that overexpression of ICSBP negatively regulated normal hematopoiesis. These data provide direct evidence that ICSBP can act as a tumor suppressor that regulates normal and neoplastic proliferation of hematopoietic cells.