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PNAS:原癌基因ROR1促进白血病进程

来源:生物谷 2014-01-03 19:35

2014年1月4日讯 /生物谷BIOON/--加州大学科学家报道称原癌基因ROR1仅在慢性淋巴细胞性白血病(chronic lymphocytic leukemia,CLL)的B细胞中表达,在正常组织中不表达。而且该基因与其他原癌基因共同作用会加速小鼠的CLL发病进程。相关报道发表在近期的PNAS杂志上。

Thomas Kipps博士领导的研究团队对ROR1基因进行了大量的研究。如他们研究发现ROR1与上皮细胞间质化过程相关。CLL癌细胞通过ROR1进行扩散,而90%病人的死因都是由于癌细胞扩散。

在本次研究中,Kipps博士领导的研究团队创建了表达人类ROR1的转基因小鼠,发现该小鼠产生的B细胞发生异常,与人类CLL细胞很类似。而非转基因小鼠中却没有该异常B细胞。

接着科学家将该转基因小鼠与另一种原癌基因TCL1转基因小鼠杂家,发现具有ROR1和TCL1的子代小鼠会发展称恶性CLL。

当科学家用抗ROR1抗体治疗小鼠后,CLL细胞遭到破坏,而且对治疗更敏感。基于该发现,Kipps博士计划在2014年进行临床试验,检测人源化ROR1抗体治疗白血病的效果。(生物谷Bioon.com)

doi:10.1073/pnas.1308374111

ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice

George F. Widhopf II, Bing Cui, Emanuela M. Ghia, Liguang Chen, Karen Messer, Zhouxin Shen, Steven P. Briggs, Carlo M. Croce, and Thomas J. Kipps

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell–restricted expression of ROR1 and could develop clonal expansions of ROR1brightCD5+B220low B cells resembling human CLL at ≥15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eμ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5+B220low B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1. Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell–cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of Ki-67–positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL.

 

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