title: ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice.
abstract: 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 ROR1(bright)CD5(+)B220(low) 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(+)B220(low) 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.
authors.affiliation: Departments of Medicine and Biostatistics/Bioinformatics and Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.forename: Zhouxin
authors.initials: Z
authors.lastname: Shen
authors.forename: Steven P
authors.initials: SP
authors.lastname: Briggs
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; immune therapy; monoclonal antibody; mouse model