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: George F Widhopf 2nd, Bing Cui, Emanuela M Ghia, Liguang Chen, Karen Messer, Zhouxin Shen, Steven P Briggs, Carlo M Croce, Thomas J Kipps
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 2 Pg. 793-8 (Jan 14 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24379361 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Proto-Oncogene Proteins
• Tcl1 protein, mouse
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Age Factors
• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (physiology)
• B-Lymphocytes (metabolism)
• Carcinogenesis (metabolism)
• Cell Adhesion (physiology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism)
• Mice
• Mice, Transgenic
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (immunology, metabolism)