Neoantigenic receptor ROR1 promotes cell growth through diverse and complementary mechanisms.

Aberrant expression of neoantigenic receptor ROR1 has been identified in diverse lymphomas, including mantle cell lymphoma (MCL) and in a broad spectrum of nonlymphoid malignancies. While ROR1 has emerged as an attractive therapeutic target, its oncogenic role and the underlying mechanisms remain rather poorly characterized. Focusing on MCL, we found that ROR1 expression is heterogeneous and it can be induced under environmental stress. Inhibition of ROR1 expression resulted in cell-cycle suppression and apoptotic cell death. The ROR1 loss affected expression of numerous genes and altered phosphorylation of many proteins, including those involved in cell-cycle progression. ROR1 also promotes the synthesis of pyrimidines and purines, including induction of phosphorylation of enzymes involved in pyrimidine synthesis. Finally, we found that ROR1 induced phosphorylation of DEK and that its depletion abrogates ROR1 expression. These results provide insights into the multi-faceted oncogenic role of ROR1, further justifying targeting ROR1 in MCL and other malignancies.