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

Significance Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a type 1 protein expressed on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. This study demonstrates that ROR1 can contribute to leukemogenesis and can bind to T-cell leukemia 1 (TCL1), a known coactivator of AKT. ROR1 can accelerate leukemogenesis when expressed together TCL1, leading to increased activation of AKT and enhanced leukemia-cell proliferation and resistance to apoptosis. Treatment of ROR1-expressing leukemia cells with an anti-ROR1 mAb could down-modulate ROR1, reduce phospho-AKT, and impair their capacity to engraft syngeneic mice. Collectively, our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL. 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.