Editors' ChoiceCancer

ROR1 Generates Bad Blood

Science Signaling  21 Jan 2014:
Vol. 7, Issue 309, pp. ec19
DOI: 10.1126/scisignal.2005082

The expression of the gene for receptor tyrosine kinase–like orphan receptor 1 (ROR1) is increased in several cancers, including B cell chronic lymphocytic leukemia (CLL), and antibody- and engineered T cell–based therapies targeting ROR1 show efficacy in preclinical models. ROR1 is a single-pass transmembrane receptor that binds Wnt ligands and lacks intrinsic kinase activity. ROR1-positive CLL cells are usually also positive for TCL1, an oncoprotein that in leukemic cells binds to and enhances the activity of AKT, a kinase that promotes cellular proliferation and survival. Transgenic (Tg) mice expressing TCL1 in B cells develop CLL-like leukemia between 13 and 18 months of age. Widhopf II et al. found that ROR1 synergized with TCL1 to promote B cell transformation. Tg mice that expressed human ROR1 in B cells had normal B cells until 15 months of age, at which point a small percentage of mice developed symptoms characteristic of human CLL patients, including lymphocytosis and splenomegaly due to accumulation of ROR1-positive malignant B cells. ROR1 and TCL1 coimmunoprecipitated from patient-derived CLL cells, and mice that expressed both ROR1 and TCL1 in B cells (ROR1 X TCL1 Tg mice) showed accelerated onset of CLL-like symptoms. Compared with B cells from TCL1 Tg mice, B cells from ROR1 X TCL1 Tg mice had increased expression of genes encoding proteins that associate with AKT, increased phosphorylation and activation of AKT, and enhanced survival, proliferation, and engraftment potential in recipient ROR1 Tg mice. Monoclonal antibodies targeting ROR1 reduced the activation of AKT in cultured B cells from ROR1 X TCL1 mice and inhibited leukemogenesis when injected into ROR1 Tg mice engrafted with ROR1 X TCL1 B cells. Thus, ROR1-based therapies may inhibit the progression of B cell CLL, and potentially other cancers, by reducing the ability of TCL1 to enhance activation of AKT.

G. F. Widhopf II, B. Cui, E. M. Ghia, L. Chen, K. Messer, Z. Shen, S. P. Briggs, C. M. Croce, T. J. Kipps, ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 111, 793–798 (2014). [Abstract] [Full]