期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：2
页码：793-798
DOI：10.1073/pnas.1308374111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 E{micro}-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 x TCL1) developed CD5+B220low B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 x 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 x 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 x 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 x TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL.
关键词：mouse model ; monoclonal antibody ; AKT ; immune therapy
